万字长文：从理论到生产，一文读懂mRNA-LNP制剂技术
<div style="max-width:100%;overflow:hidden;"><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: center;margin-bottom: 24px;line-height: 2em;text-indent: 0em;" data-mpa-powered-by="yiban.io"><strong style="color: rgb(16, 101, 230); font-family: "Microsoft YaHei", SimHei, Verdana, Arial, sans-serif; font-size: 14px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 17px;">文章速览</span></strong></section><section data-mpa-template="t" mpa-from-tpl="t"><section style="display: flex;justify-content: center;align-items: center;width: 100%;" data-mid="" mpa-from-tpl="t"><section style="display: flex;justify-content: flex-start;align-items: center;flex-direction: column;width: 100%;padding: 0px 4px 0px 13px;" data-mid="" mpa-from-tpl="t"><section style="width: 63px;height: 18px;display: flex;justify-content: center;align-items: center;align-self: center;z-index: 2;margin-bottom: -5.1px;" data-mid="" mpa-from-tpl="t"></section><section style="width: 110px;height: 8px;background: #FFFFFF;z-index: 1;" data-mid="" mpa-from-tpl="t"><br></section><section style="width: 100%;background: rgb(16, 101, 230);border-radius: 6px;" data-mid="" mpa-from-tpl="t"><section style="width: 100%;text-align: left;padding: 14px 10px 14px 12px;background: rgb(255, 255, 255);border-radius: 6px;border-width: 1px;border-style: solid;border-color: rgb(16, 101, 230);transform: translate(-4.1px, -4.1px);" data-mid="" mpa-from-tpl="t"><p style="margin: 0px;padding: 0px;clear: both;min-height: 1em;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;"><span style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(16, 101, 230);"><strong style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;">一、LNP的历史</span></strong></span></p><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">1.1 核酸药物</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">1.2 核酸药物传递系统是关键</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">1.3 核酸递送系统</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">1.4 组装过程</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">1.5 mRNA-LNP制剂的质量要求</span></section><p style="margin: 0px;padding: 0px;clear: both;min-height: 1em;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;"><span style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(16, 101, 230);"><strong style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;">二、LNP的处方和成分作用</span></strong></span></p><p style="margin: 0px;padding: 0px;clear: both;min-height: 1em;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;"><span style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(16, 101, 230);"><strong style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;">三、核酸递送LNP的关键辅料</span></strong></span></p><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">3.1 阳离子脂质</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">3.2 胆固醇</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">3.3 辅助型脂质</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">3.4 聚乙二醇化磷脂</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">3.5 稳定剂蔗糖或海藻糖等</span></section><p style="margin: 0px;padding: 0px;clear: both;min-height: 1em;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;"><span style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(16, 101, 230);"><strong style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;">四、核酸递送LNP的氮磷比计算</span></strong></span></p><p style="margin: 0px;padding: 0px;clear: both;min-height: 1em;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;"><span style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(16, 101, 230);"><strong style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;">五、制备理论方法</span></strong></span></p><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">5.1 微流控技术基本原理</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">5.2 冲击式射流混合法</span></section><p style="margin: 0px;padding: 0px;clear: both;min-height: 1em;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;"><span style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(16, 101, 230);"><strong style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;">六、切向流过滤（TFF）</span></strong></span></p><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">6.1 中空纤维 vs. 平板膜包</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">6.2 一次性使用 vs. 重复使用</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">6.3 “切向流”泵选择</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">6.4 工艺参数</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">6.5 切向流过滤采用从实验室到中试、再到商业化生产的综合TFF解决方案</span></section><p style="margin: 0px;padding: 0px;clear: both;min-height: 1em;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;"><span style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(16, 101, 230);"><strong style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;">七、mRNA疫苗传递系统性能的决定因素</span></strong></span></p><p style="margin: 0px;padding: 0px;clear: both;min-height: 1em;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;"><span style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(16, 101, 230);"><strong style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;">八、mRNA-LNP的设计简介</span></strong></span></p><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">8.1 LNP配方注意事项</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">8.2 聚乙二醇（PEG）脂质</span></section><section style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;text-indent: 2em;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;color: rgb(74, 75, 76);">8.3 长期保存</span></section><p style="margin: 0px;padding: 0px;clear: both;min-height: 1em;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;"><span style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(16, 101, 230);"><strong style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;">九、核酸递送LNP国内发展的问题</span></strong></span></p><p style="margin: 0px;padding: 0px;clear: both;min-height: 1em;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(51, 51, 51);font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 16px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;white-space: normal;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(230, 245, 255);text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;"><span style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;color: rgb(16, 101, 230);"><strong style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;"><span mpa-is-content="t" style="margin: 0px;padding: 0px;max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;letter-spacing: 1px;font-size: 15px;">十、小结</span></strong></span></p></section></section></section></section></section><p><br></p><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section mpa-from-tpl="t"><section style="margin-top: 10px;margin-bottom: 10px;text-align: center;font-size: 13px;text-indent: 0em;"><section mpa-from-tpl="t" style="padding-top: 0.5em;padding-right: 0.2em;display: inline-block;"><section mpa-from-tpl="t" style="padding: 3px;display: inline-block;vertical-align: top;width: 3em;height: 3em;border-color: rgb(16, 101, 230);border-style: solid;border-width: 1px;border-radius: 100%;"><section mpa-from-tpl="t" style="width: 30.5px;height: 31px;border-radius: 100%;background-color: rgb(16, 101, 230);color: rgb(255, 255, 255);font-size: 19px;line-height: 1.4;"><p style="clear: both;min-height: 1em;" mpa-is-content="t">一</p></section></section><section mpa-from-tpl="t" style="margin-left: -0.5em;display: inline-block;vertical-align: top;width: 6px;height: 6px;border-radius: 100%;background-color: rgb(16, 101, 230);"><br mpa-from-tpl="t"></section></section></section></section></section></section><section style="margin-top: 0.5em;margin-bottom: 0.5em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t" mpa-is-content="t">LNP的历史</strong></section><section style="margin-top: 0.5em;margin-bottom: 1em;clear: both;min-height: 1em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t"></strong></section></section></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 0px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">1.1 核酸药物</span></h2></section></section><p style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-indent: 0em;line-height: 2em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">2020年新冠疫情在全球范围爆发，整个世界对新冠疫苗的需求量日益增大，Moderna及Pfizer/BioNTech的mRNA新冠疫苗陆续上市后，行业逐渐认识到mRNA（信使核糖核酸）<span style="color: rgb(74, 75, 76);font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: 1px;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;display: inline !important;float: none;">新冠</span><span style="color: rgb(74, 75, 76);font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: 1px;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;display: inline !important;float: none;">疫</span><span style="color: rgb(74, 75, 76);font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: 1px;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;display: inline !important;float: none;">苗</span>/药物的可行性与优势<sup> </sup>。</span></p><p style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">脱氧核糖核酸（DNA）和核糖核酸（RNA）的主要作用是携带和传递遗传信息。这两类分子能够用于疾病的预防、诊断和治疗的，就是核酸药物。核酸药物包括反义核酸（ASO）、小干扰RNA（siRNA）、微小RNA（miRNA）、小激活RNA（saRNA）、信使RNA（mRNA）适配体（aptamer）、核酶(ribozyme)、抗体核酸偶联药物（ARC）等，是基因治疗的一种形式。</span></p><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="color: rgb(74, 75, 76);font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;text-indent: 0em;">核酸药物的优点是可以简单地通过重新排列A，G，C，T（U）的序列而成为新的药物。核酸药物能够以化学药物或抗体药物无法靶向（例如mRNA和miRNA）的分子作为作用靶点，有望对传统药物疗效不佳的疾病产生突破性的进展，比如难以治疗的遗传疾病、癌症以及某些病毒感（例如SARS-CoV-2）。</span></section><section><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">1.2 核酸药物传递系统是关键</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">核酸药物的开发主要面临三大问题：</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;margin-bottom: 0px;text-indent: 0em;"><strong><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">1.2.1.核酸分子在体内不稳定性；</span></strong></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;margin-bottom: 0px;text-indent: 0em;"><strong><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">1.2.2.核酸分子潜在的副作用；</span></strong></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;margin-bottom: 0px;text-indent: 0em;"><strong><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">1.2.3.核酸药物递送系统开发难度大。</span></strong></section><section style="text-indent: 0em;"><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">1.3 核酸递送系统</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">其中重要的是递送系统的研发。核酸药物在其注射进入人体后，如何存留足够时间以准确靶向到病变部位，同时避免损伤正常细胞，必须是研发出高效安全的药物递送系统，以解决核酸药物递送、稳定性、脱靶效应等难题。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">递送系统可分为病毒载体和非病毒载体，病毒载体在基因治疗中应用较多，但由于其免疫原性、致瘤性、和有限的载药量（loading capacity）使得其在核酸药物中应用相对较少；而非病毒载体应用相对更多，如聚合物类（polymer）、脂质类（liposome或LNP）；且可以将核酸药物与特定的配体结合使其能够靶向特定的细胞，如GalNAc、多肽、抗体等。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">脂质纳米颗粒（Lipid Nanoparticle，LNP）是目前核酸药物研究应用多的递送系统之一，LNP能够安全而有效地递送核酸。目前已经有使用LNP的核酸药物获批，例如Alnylam公司获批的siRNA药物Onpattro。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">LNP是目前比较成熟的一个技术平台，用来递送RNA药物、疫苗或基因编辑工具。相对其他类型的核酸药物递送系统而言，LNP具有很多优势，比如核酸包封率高并且能够有效转染细胞，组织穿透性强，细胞毒性和免疫原性低，更有利于递送药物等优势，这些优势使LNP成为出色的核酸递送系统。</span></section><section style="margin-top: 0pt;text-align: center;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;margin-bottom: 0px;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;"><shape type="#_x0000_t75" filled="f" style="text-indent:0;left:0;width:497.33228pt;height:164.0656pt;"><imagedata title="image1"></imagedata></shape></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: center;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;line-height: 115%;letter-spacing: 1px;font-size: 12px;color: rgb(149, 151, 153);">mRNA-LNP的组成</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">LNP的修饰和工程处理推动了更加先进的脂质纳米颗粒的改进。先进LNP开发的关键原则在于结构以及应用方面，前者包括LNP的生物相容性、LNP的流动性、相态和相变温度、电荷（zeta电势）、粒径以及包封效率和稳定性；后者包括毒性、循环时间、细胞摄入以及载荷释放等。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">目前，LNP在有效性、选择性以及药物的体内分布方便实现了显著的优化，同时降低了传统药物载体系统的毒性和局限性。不同类型的LNP有不同的优势和缺点，这决定了它们在不同治疗药物中的应用。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">一种新兴的药物类型是核酸治疗药物，其显示具有治疗多种疾病的潜力。第一个获得批准的此类药物是Patisiran（ONPATTRO），一种使用LNP制剂的小干扰RNA（siRNA），用于减少肝内转甲状腺素蛋白的形成，以治疗遗传性转甲状腺素介导的淀粉样变性。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: center;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;"></span></section><section style="margin-bottom: 0px;text-indent: 0em;"><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">1.4 组装过程</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">如图所示，这些溶液中LNP的组装和形成是由疏水力和静电力驱动的，先将四种脂质（解离性脂类、饱和磷脂脂类、胆固醇脂类、聚乙二醇脂类）溶于乙醇中，不存在任何反离子，因此可电离脂质呈电中性（图A）。</span></section><p style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">1体积的含脂质乙醇溶液通常与3体积的mRNA在pH=4的醋酸盐水缓冲液中混合，当脂质与水缓冲液接触时，它们在3:1的水/乙醇溶剂中变得不溶，并且可电离脂质变得质子化并且带正电荷，然后驱动它与带负电荷的mRNA磷酸骨架静电结合（图B），同时脂质变得不溶，形成脂质颗粒，将mRNA包裹在主要的水悬浮液中。通过改变PEG的摩尔分数，可以预测LNP的大小。水相和脂质相的初始混合产生接近5.5的pH值，使可电离脂质质子化，其具有接近6.5的LNP pKa，并且允许mRNA结合和包封（图C）。随后通过稀释、透析或切向流过滤提高pH值，中和可电离脂质，直到其在pH值为7.4时形成了不带电的纳米脂质颗粒（图D）。使用FRET对证实了融合，PEG可以控制LNP的最终大小。</span></p><section style="text-indent: 0em;"><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">1.5 mRNA-LNP制剂的质量要求</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">根据2018年4月FDA “Liposome Drug Products”（脂质体药物产品）行业指南，mRNA原液药的放行及表征测试需要包括以下几个关键点：<span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-weight: bold;">多分散性指数PDI、Zeta电位、mRNA鉴别和浓度、mRNA包封效率(%)、脂质特性和纯度、pH值和渗透压、残留溶剂和无菌性、稳定性、均匀性等。</span></span></section><section style="margin-top: 0pt;text-align: center;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;margin-bottom: 0px;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;"></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: center;line-height: 2em;margin-bottom: 24px;text-indent: 0em;"><span style="line-height: 115%;font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;letter-spacing: 1px;font-size: 12px;color: rgb(149, 151, 153);">mRNA-LNP成品(drug product)部分放行标准</span></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t" style="color: rgb(51, 51, 51);font-size: 17px;text-align: justify;"><section data-mpa-template="t" mpa-from-tpl="t"><section mpa-from-tpl="t"><section style="margin-top: 10px;margin-bottom: 10px;text-align: center;font-size: 13px;text-indent: 0em;"><section mpa-from-tpl="t" style="padding-top: 0.5em;padding-right: 0.2em;display: inline-block;"><section mpa-from-tpl="t" style="padding: 3px;display: inline-block;vertical-align: top;width: 3em;height: 3em;border-color: rgb(16, 101, 230);border-style: solid;border-width: 1px;border-radius: 100%;"><section mpa-from-tpl="t" style="width: 30.5px;height: 31px;border-radius: 100%;background-color: rgb(16, 101, 230);color: rgb(255, 255, 255);font-size: 19px;line-height: 1.4;"><p style="clear: both;min-height: 1em;" mpa-is-content="t">二</p></section></section><section mpa-from-tpl="t" style="margin-left: -0.5em;display: inline-block;vertical-align: top;width: 6px;height: 6px;border-radius: 100%;background-color: rgb(16, 101, 230);"><br mpa-from-tpl="t"></section></section></section></section></section></section><section style="margin-top: 0.5em;margin-bottom: 0.5em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t" mpa-is-content="t">LNP的处方和成分作用</strong></section><section style="margin-top: 0.5em;margin-bottom: 1em;clear: both;min-height: 1em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t"></strong></section></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">LNP是由可电离脂质、饱和磷脂（DSPC）、胆固醇和聚乙二醇（PEG）四种脂质组成的稳定的纳米颗粒。可电离脂质促进mRNA自主聚集成病毒大小的颗粒和mRNA在细胞质中的释放，PEG延长了复合物的半衰期，胆固醇作为一种稳定剂，可提高复合物的稳定性，磷脂支持形成脂质双层结构。通过调节四者之间的比例可以调控LNP的大小。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">一些公司在核酸递送系统的脂质配比上是非常相似的，LNP的配方中可离子化阳离子脂质占50%，剩下10%是中性脂质，38-40%是胆固醇。脂质纳米颗粒（LNP）模拟细胞膜形成细胞，直径只有100纳米左右，成分包括中性脂质、阳离子脂质、胆固醇、PEG-脂质。核酸药物与普通化学药物的明显区别是核酸有数量庞大的磷酸根，因而呈负电，使用可离子化阳离子脂质的LNP可以更好的包裹核酸药物。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">阳离子脂质有一个带铵根的亲水端，在酸性下与氢离子结合呈正电，借助两者的静电吸附，就能够将核酸包裹在脂质纳米粒中。当LNP被细胞内吞后，可离子化阳离子脂质会在酸性环境下离子化，破坏内涵体膜，从而实现LNP的内涵体逃逸。LNP还可以设计成特异性结合载脂蛋白如APOE3，APOE3会将LNP带到肝脏，LNP和肝细胞表面受体结合后通过细胞内吞作用释放药物，起到靶向肝细胞的目的，包裹后的LNP外壳因阳离子脂质的疏水端向外而呈疏水性，此时可以加入传统脂质体合成中常用的一端修饰有PEG的脂质——PEG-脂质，使PEG-脂质的疏水端与阳离子脂质的疏水端结合，而PEG-脂质的亲水端（连有PEG）则向外形成核酸脂质纳米粒的外壳。为了增加核酸脂质纳米粒的稳定性，还可以添加适量的胆固醇等成分，使PEG-脂质的疏水端与阳离子脂质的疏水端结合更为紧密，得到核酸脂质纳米粒的成品。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;margin-bottom: 24px;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">2018年临床批准的第一个siRNA产品的开发主要集中在优化可电离脂质，其次是PEG脂质和LNP中使用的四种脂质的比率，以及LNP组装和制造程序。用于mRNA的LNP配方通常包括多个组成部分，其主要功能成分为可离子化阳离子脂质，通常占整个结构的50%左右，它们在形成过程中促进核酸的捕获，在循环过程中帮助维持中性电荷，并促进细胞内运输。然后是胆固醇，约占结构的40%，由于它的疏水性，有助于提供刚性、配方稳定性并支持控释。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;margin-bottom: 24px;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">之后是PEG脂质成分，约1-2%，这有助于控制和维持颗粒粒径，并通过防止血液中的调理素作用，延长循环时间。最后10%左右的配方由结构脂质成分组成，如DSPC和DOPE，其有助于提供配方的整体结构稳定性，以及在生产和长期存储期间的稳定性。通过优化LNP，可显著提高基于LNP-mRNA的治疗药物的安全性和有效性，包括针对不同应用路径的可电离脂质和可生物降解脂质的创新；LNP-mRNA组成优化，如改变脂质比例或脂质-mRNA比例；创新隐形脂质；以及通过针对特定组织的定位和LNP-mRNA治疗药物对特定细胞类型和器官的主动靶向，改善当前的脱靶效应，并为难以靶向的组织的新应用铺平道路。</span></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t" style="color: rgb(51, 51, 51);font-size: 17px;text-align: justify;"><section data-mpa-template="t" mpa-from-tpl="t"><section mpa-from-tpl="t"><section style="margin-top: 10px;margin-bottom: 10px;text-align: center;font-size: 13px;text-indent: 0em;"><section mpa-from-tpl="t" style="padding-top: 0.5em;padding-right: 0.2em;display: inline-block;"><section mpa-from-tpl="t" style="padding: 3px;display: inline-block;vertical-align: top;width: 3em;height: 3em;border-color: rgb(16, 101, 230);border-style: solid;border-width: 1px;border-radius: 100%;"><section mpa-from-tpl="t" style="width: 30.5px;height: 31px;border-radius: 100%;background-color: rgb(16, 101, 230);color: rgb(255, 255, 255);font-size: 19px;line-height: 1.4;"><p style="clear: both;min-height: 1em;" mpa-is-content="t">三</p></section></section><section mpa-from-tpl="t" style="margin-left: -0.5em;display: inline-block;vertical-align: top;width: 6px;height: 6px;border-radius: 100%;background-color: rgb(16, 101, 230);"><br mpa-from-tpl="t"></section></section></section></section></section></section><section style="margin-top: 0.5em;margin-bottom: 0.5em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t" mpa-is-content="t">核酸递送脂质纳米颗粒（LNP）的关键辅料</strong></section><section style="margin-top: 0.5em;margin-bottom: 1em;clear: both;min-height: 1em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t"></strong></section></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;margin-bottom: 0px;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">核酸递送脂质纳米颗粒一般由以下辅料组成：</span></section><section style="text-indent: 0em;"><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">3.1 阳离子脂质</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;margin-bottom: 0px;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">与带负电的 mRNA 结合，可高效包载核酸药物，同时提供正电荷，与带负电荷的mRNA复合，有助于内涵体逃逸，mRNA体内转染，可离子化脂质具有pH敏感性。具体产品有DOTAP, Cl，DLin-MC3-DMA，DC-CHOL等。</span></section><section style="text-indent: 0em;"><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">3.2 胆固醇</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;margin-bottom: 0px;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">稳定LNP结构，调节膜流动性，提高粒子稳定性。</span></section><section style="text-indent: 0em;"><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">3.3 辅助型脂质</span></h2></section></section><p style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">常用DOPE等，稳定粒子，破坏内涵体稳定性，提高核酸递送效率。</span></p><p style="margin-bottom: 0px;"><br></p><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">3.4 聚乙二醇化磷脂</span></h2></section></section><p style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">提高粒子稳定性，减少粒子在体内与血浆蛋白的结合，延长体循环时间。例如DMG-PEG2000，DSPE-MPEG2000（药用注射级）等。</span></p><section><br mpa-from-tpl="t"></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 0px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">3.5 稳定剂蔗糖或海藻糖等<span style="display: none;line-height: 0px;"></span></span></h2></section></section><p style="text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;margin-top: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">提高LNP和mRNA疫苗的稳定性，防止脂质黏性过大，提高。</span></p><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t" style="color: rgb(51, 51, 51);font-size: 17px;text-align: justify;"><section data-mpa-template="t" mpa-from-tpl="t"><section mpa-from-tpl="t"><section style="margin-top: 10px;margin-bottom: 10px;text-align: center;font-size: 13px;text-indent: 0em;"><section mpa-from-tpl="t" style="padding-top: 0.5em;padding-right: 0.2em;display: inline-block;"><section mpa-from-tpl="t" style="padding: 3px;display: inline-block;vertical-align: top;width: 3em;height: 3em;border-color: rgb(16, 101, 230);border-style: solid;border-width: 1px;border-radius: 100%;"><section mpa-from-tpl="t" style="width: 30.5px;height: 31px;border-radius: 100%;background-color: rgb(16, 101, 230);color: rgb(255, 255, 255);font-size: 19px;line-height: 1.4;"><p style="clear: both;min-height: 1em;" mpa-is-content="t">四</p></section></section><section mpa-from-tpl="t" style="margin-left: -0.5em;display: inline-block;vertical-align: top;width: 6px;height: 6px;border-radius: 100%;background-color: rgb(16, 101, 230);"><br mpa-from-tpl="t"></section></section></section></section></section></section><section style="margin-top: 0.5em;margin-bottom: 0.5em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t" mpa-is-content="t">核酸递送脂质纳米颗粒（LNP）的氮磷比计算</strong></section><section style="margin-top: 0.5em;margin-bottom: 1em;clear: both;min-height: 1em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t"></strong></section></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">在核酸脂质纳米颗粒合成时，正电荷与负电荷的数量比将影响到纳米粒子的稳定性、电位等性能。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">正电荷通常为具有可电离铵根（N）的阳离子脂质，而负电荷则为带有大量磷酸根（P）的核酸分子，两者可通过静电吸附的方式结合在一起。两者不合理的比例可能会导致粒径过大、稳定性差等缺陷，正确计算正电荷与负电荷的比（N/P比）是非常重要的。在实际应用中，也可以先定下N/P比，再确定有机相或水相的浓度，此时只需要逆向计算即可。</span></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t" style="color: rgb(51, 51, 51);font-size: 17px;text-align: justify;"><section data-mpa-template="t" mpa-from-tpl="t"><section mpa-from-tpl="t"><section style="margin-top: 10px;margin-bottom: 10px;text-align: center;font-size: 13px;text-indent: 0em;"><section mpa-from-tpl="t" style="padding-top: 0.5em;padding-right: 0.2em;display: inline-block;"><section mpa-from-tpl="t" style="padding: 3px;display: inline-block;vertical-align: top;width: 3em;height: 3em;border-color: rgb(16, 101, 230);border-style: solid;border-width: 1px;border-radius: 100%;"><section mpa-from-tpl="t" style="width: 30.5px;height: 31px;border-radius: 100%;background-color: rgb(16, 101, 230);color: rgb(255, 255, 255);font-size: 19px;line-height: 1.4;"><p style="clear: both;min-height: 1em;" mpa-is-content="t">五</p></section></section><section mpa-from-tpl="t" style="margin-left: -0.5em;display: inline-block;vertical-align: top;width: 6px;height: 6px;border-radius: 100%;background-color: rgb(16, 101, 230);"><br mpa-from-tpl="t"></section></section></section></section></section></section><section style="margin-top: 0.5em;margin-bottom: 0.5em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t" mpa-is-content="t">制备理论方法</strong></section><section style="margin-top: 0.5em;margin-bottom: 1em;clear: both;min-height: 1em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t"></strong></section></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">常用的脂质纳米颗粒制备方法主要有薄膜水化法、挤出法、均质法等。</span></section><p style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">目前先进的采用微流控混合技术来制备核酸脂质纳米颗粒，该方法相对简便快速，条件温和，同时容易实现生产放大。通过不同生产规模的微流控机器，可以较好的实现mRNA-LNP的良好制备，其结果一致性良好，粒径结果合适，且具有极低的PDI值，证实其分散性较好，并且包封效果可达90%以上。通过微流控技术高效、可放大的制备核酸脂质纳米粒，一般最多每小时可生产20升左右。</span></p><p><br></p><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">5.1 微流控技术基本原理</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">将脂质与核酸分别溶解在水相和有机相后，将两相溶液注入制备系统的两条入口通道，一端是RNA的水溶液，一端是脂质的乙醇溶液，通过两相的快速混合，完成核酸脂质纳米颗粒的合成。</span></section><p style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">改变流体注入速度和比率，可以控制脂质纳米颗粒的粒径大小。</span></p><p><br></p><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">5.2 冲击式射流混合法</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">可以实现大生产，利用高压泵，让疫苗和脂质溶液形成两股射流，在腔体中进行对冲，利用流体动力学让脂质各个组分充分地混合，形成包裹mRNA的纳米LNP</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">生产设备碰撞喷射混合器安装在洁净间（C级）内，通过中控平台控制工艺步骤中所有单元的流量。所有单元安装在不锈钢框架内，以适应药品生产中的 CIP清洁程序。该系统包括：KNAUER 碰撞喷射混合器（IJM）， 脂质/乙醇混合物和 mRNA/缓冲液混合物的入口管路，脂质体出口管路，CIP在线清洁系统和不锈钢框架。</span></section><p style="margin-top: 0pt;text-align: center;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;"></span></p><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: center;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;letter-spacing: 1px;font-size: 12px;color: rgb(149, 151, 153);">mRNA-LNP制剂工艺流程</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">mRNA-LNP<span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-weight: bold;">制剂工艺的质控也至关重要。</span>将制备好的mRNA经由微流控等设备进行脂质纳米颗粒LNP包裹，过程中<span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-weight: bold;">通过优化总流量和流量比来获得理想的粒径尺寸</span>，由于微流控的两相溶液分别为溶解于酸性水相的核酸以及溶解于有机相的脂类，在这样复杂的混合溶液下，需要在包裹后进行缓冲液置换来稳定纳米脂质颗粒LNP结构，确认去除产品中残留的有机溶剂。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">mRNA<span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-weight: bold;">包裹后续工艺一般需要浓缩换液及除菌过滤，并无进一步的纯化手段，因此保障浓缩换液过程中产品质量的稳定性是非常重要。</span>在考量实现放大规模生产的稳定工艺，大多数企业会采用切向流技术取代透析手段进行洗滤换液，为了全面地考察切向流超滤工艺，需要通过QbD分析影响质量属性的关键过程参数控制<span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-weight: bold;">包含剪切力、进口流速及跨膜压差控制、换液倍数等</span>，由此可知需要通过选择切向流技术以及如何优化来确保产品的质量<sup> </sup>。</span></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t" style="color: rgb(51, 51, 51);font-size: 17px;text-align: justify;"><section data-mpa-template="t" mpa-from-tpl="t"><section mpa-from-tpl="t"><section style="margin-top: 10px;margin-bottom: 10px;text-align: center;font-size: 13px;text-indent: 0em;"><section mpa-from-tpl="t" style="padding-top: 0.5em;padding-right: 0.2em;display: inline-block;"><section mpa-from-tpl="t" style="padding: 3px;display: inline-block;vertical-align: top;width: 3em;height: 3em;border-color: rgb(16, 101, 230);border-style: solid;border-width: 1px;border-radius: 100%;"><section mpa-from-tpl="t" style="width: 30.5px;height: 31px;border-radius: 100%;background-color: rgb(16, 101, 230);color: rgb(255, 255, 255);font-size: 19px;line-height: 1.4;"><p style="clear: both;min-height: 1em;" mpa-is-content="t">六</p></section></section><section mpa-from-tpl="t" style="margin-left: -0.5em;display: inline-block;vertical-align: top;width: 6px;height: 6px;border-radius: 100%;background-color: rgb(16, 101, 230);"><br mpa-from-tpl="t"></section></section></section></section></section></section><section style="margin-top: 0.5em;margin-bottom: 0.5em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t" mpa-is-content="t">切向流过滤（TFF）</strong></section><section style="margin-top: 0.5em;margin-bottom: 1em;clear: both;min-height: 1em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t"></strong></section></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">LNP-mRNA制剂常采用交错Y（T）型微流控设备进行生产，其中，一股进样液流为处于酸性缓冲液中的mRNA，另一股进样液流为溶解在乙醇中的脂质。两股进样液流在混合通道中相遇、混合，并以单股液流流出设备。微流控设备之后，mRNA链将被包封在LNP中。此时，需要使用切向流过滤（TFF）去除mRNA-LNP之外的所有元素，包括微流控步骤使用的溶剂，并进行缓冲液置换。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">切向流过滤是生物药生产中的常见单元操作，用于目标产物的纯化、浓缩以及缓冲液置换，与直流过滤相比，其通过料液平行于膜表面切向循环流动而形成冲扫，降低污染物在膜表面的积聚以及凝胶层的形成，缓解污染，提高单位膜表面积的处理能力，且因连续循环的液流模式，可将滤液或截留液中的产物作为待回收的目标产品。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">基于膜结构设计，常见的切向流过滤方式可分别平板膜包和中空纤维两种形式。此外，影响切向流过滤步骤性能的因素还包括膜材质、膜孔径/截留分子量（MWCO）、泵驱动形式以及管路设计等配置以及诸如跨膜压（TMP）、剪切力以及过滤通量等过程参数，需根据目标产品的特性进行选择和优化，特别是对于mRNA-LNP这类对工艺过程中的外部应力条件较为敏感的产品。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: center;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;letter-spacing: 1px;font-size: 12px;color: rgb(149, 151, 153);">中空纤维及平板膜包的差异对比</span></section><section><br mpa-from-tpl="t"></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">6.1 中空纤维 vs. 平板膜包</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">中空纤维是纤维管状膜，膜壁上有过滤膜孔，不同数量的纤维灌封在管状外壳内，形成过滤组件，每根中空纤维的内腔是开放式的流道，所以中空纤维内的液流处于一种接近温和层流的状态。平板膜包是多层平面膜堆叠在一起，中间以间隔筛网隔开，形成流道，平板膜包内的液流状态更接近湍流，以提高对膜表面的冲洗作用。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">多数情况下，如目标产品对剪切影响较为敏感，采用基于中空纤维的切向流过滤形式更有利于保护产品的结构完整性，而平板膜包内的湍流促进效果以及其可耐受更高操作压力的特点，在其它条件相似的情况下，可能使其获得更高的通量。对于mRNA-LNP，可优先选择测试中空纤维过滤器形式，以保证完整产物的收率，对于大部分目标产品类型，其可获得良好的结果； </span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">但对于结构更为稳定的产品，平板膜包可能在可以不影响产品完整性的情况下，获得更高的通量。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">从两种切向流技术观察工艺性能表现，相比中空纤维温和的层流，平板膜包借由筛网构造引起的湍流会使得流体透过效率提高，因此两者在实现相近工艺滤速的情况下，中空纤维需要输出更高的进口流速。<span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-weight: bold;">膜包较高的转化率</span>（Conversion ratio）<span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-weight: bold;">可有效提升工艺效率及降低工艺能耗。</span></span></section><p style="margin-top: 0pt;text-align: center;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;"></span></p><section style="margin-top: 0pt;text-align: center;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="color: rgb(136, 136, 136);font-family: system-ui, -apple-system, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 12px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: 1.5px;orphans: 2;text-align: center;text-indent: 0px;text-transform: none;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;background-color: rgb(255, 255, 255);text-decoration-style: initial;text-decoration-color: initial;float: none;display: inline !important;">中空纤维与平板膜包的滤速性能表现对比</span></section><section><br></section><p style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">进一步针对纳米脂质颗粒LNP较为敏感的特性来看，<span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-weight: bold;">选择采用低剪切力的中空纤维方式进行浓缩换液可较好的保护产品完整性，但部分产品在包封后需先进行大量缓冲液稀释（10-20倍）来稳定产品结构，导致最终超滤浓缩倍数要求提高，使得整体超滤工艺时间过长，料液反复在系统中循环反而对产品质量造成影响。</span>在确保产品质量属性稳定的基础上（包含粒径以及PDI变化等），再进一步根据工艺需求选择最合适的切向流技术。</span></p><section><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">6.2 一次性使用 vs. 重复使用</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">一次性使用在操作简便性、灵活性、节省时间以及清洗缓冲液使用等方面的优势，已经逐渐得到行业的认可，现在，生物药生产链中的绝大部分步骤均已可实现基于一次性技术的操作，对于切向流过滤，包括中空纤维和平板膜包，均有成熟的一次性使用解决方案，且结合优化的管路设计，可进一步实现封闭式的无菌操作。</span></section><p style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">对于mRNA-LNP，由于脂质成分的使用，如采用重复使用方式，可能会对清洗步骤造成额外的挑战，特别是加上需要防爆或防静电设置的乙醇等溶剂的影响。当然，从生产规划角度看，经济性是一个重要考量因素，需要根据计划的生产规模，建立纳入各方面因素的经济性模型，包括膜包本身的成本、重复使用时的使用次数、清洗缓冲液成本以及储存和验证的相关影响等等，最终结果可能因生产规模、工厂条件、项目运营规划而有不同。</span></p><p style="margin-bottom: 0px;"><br></p><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">6.3 “切向流”泵选择</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">泵是提供“切向流”以及驱动滤液通过膜所需的跨膜压的来源。目前，有多种不同的泵形式被用于切向流过滤，包括蠕动泵、隔膜泵以及磁力离心泵等。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">蠕动泵通过连续挤压软管来驱动料液流动，因料液与泵无接触，所以不容造成污染；隔膜泵基于类似心脏跳动的原理，采用四柱塞隔膜技术，可通过缓慢“心跳”柔和泵送，四个隔膜的每个冲程均由连接至电机的偏心轴产生，采用该运行方式，泵可轻缓、安全、平稳泵送料液；磁力离心泵基于磁悬浮原理，泵叶轮无接触地悬浮于密封壳体内，并由电机磁场驱动，从而产生连续平稳的流量。</span></section><p style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">针对不同的目标产物条件和处理规模，可根据一定的参数选择合适的泵形式和尺寸，如特定的输出流量要求以及一次性/可重复使用选择。如样品处理量极低时，可选择蠕动泵，以降低系统的最低运行体积要求；如目标产品较不稳定，即使仅蠕动泵的挤压也易受破坏时，可尝试隔膜泵或磁力离心泵。</span></p><section><br mpa-from-tpl="t"></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">6.4 工艺参数</span></h2></section></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">切向流过滤的主要工艺参数包括切向流速（也称错流流速）、跨膜压（TMP）、滤液通量、剪切力等，且各个因素之间又存在相互影响。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">切向流速是流经膜表面的实际循环流速，是对膜表面形成冲扫作用的来源，切向流速越高，冲扫作用越强，膜污染的几率越低，但切向流也与流道内所形成的剪切力正相关，所以切向流速的选择应保持在对应的剪切力不影响产品质量的条件下，根据经验法则，可使用~3000-4000S-1剪切作为初始试验选择，并根据滤液通量和产品质量等结果进行调节。另一方面，TMP是驱动滤液形成的直接动力，其取决于进样压力以及通过过滤器的压力降等值，在一定操作范围内，TMP与滤液通量正相关，但在更高的TMP条件下，也更易形成膜污染，在超滤工艺中，有时会选择以恒定TMP进行操作，但随着浓缩等过程的进行，恒压条件不一定能获得稳定的滤液通量，所以恒流-恒定滤液通量也是一个可行的替代选择。</span></section><section style="margin-top: 0pt;text-align: justify;margin-left: 0pt;font-weight: normal;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">在工艺开发阶段，所有工艺参数的记录和分析是先进切向流过滤系统的重要特征，这不仅在于分析故障而获得更出色、更可重复的工艺性能，也是后续工艺规模放大和法规审计的基础。</span></section><section><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">6.5 切向流过滤采用从实验室到中试、再到商业化生产的综合TFF解决方案</span></h2></section></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">切向流过滤是mRNA-LNP工艺流程中的基本单元操作，选择合适的切向流过滤形式、系统配置以及工艺参数等工艺影响因素，是获得工艺成功的关键。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">瑞普利金提供基于不同过滤器形式（中空纤维和平板膜包）、不同泵形式（蠕动泵、隔膜泵、磁力离心泵）、不同使用策略（一次性使用和重复使用）的切向流过滤解决方案，且从规模缩小工艺开发到规模放大临床试验及商业化生产的一系列系统均具有完整的数据记录以及辅助分析功能，并可根据生产环境GMP要求进行配置，从而满足mRNA-LNP不同开发阶段的要求。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">目前用于SARS-CoV-2临床治疗的mRNA LNP的开发超滤纯化设备举例：</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: center;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;"></span></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t" style="color: rgb(51, 51, 51);font-size: 17px;text-align: justify;"><section data-mpa-template="t" mpa-from-tpl="t"><section mpa-from-tpl="t"><section style="margin-top: 10px;margin-bottom: 10px;text-align: center;font-size: 13px;text-indent: 0em;"><section mpa-from-tpl="t" style="padding-top: 0.5em;padding-right: 0.2em;display: inline-block;"><section mpa-from-tpl="t" style="padding: 3px;display: inline-block;vertical-align: top;width: 3em;height: 3em;border-color: rgb(16, 101, 230);border-style: solid;border-width: 1px;border-radius: 100%;"><section mpa-from-tpl="t" style="width: 30.5px;height: 31px;border-radius: 100%;background-color: rgb(16, 101, 230);color: rgb(255, 255, 255);font-size: 19px;line-height: 1.4;"><p style="clear: both;min-height: 1em;" mpa-is-content="t">七</p></section></section><section mpa-from-tpl="t" style="margin-left: -0.5em;display: inline-block;vertical-align: top;width: 6px;height: 6px;border-radius: 100%;background-color: rgb(16, 101, 230);"><br mpa-from-tpl="t"></section></section></section></section></section></section><section style="margin-top: 0.5em;margin-bottom: 0.5em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t" mpa-is-content="t">mRNA疫苗传递系统性能的决定因素</strong></section><section style="margin-top: 0.5em;margin-bottom: 1em;clear: both;min-height: 1em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t"></strong></section></section></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">mRNA传递系统性能的决定因素是多因素和相互作用的，包括：</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">1、其传递到适当细胞并有效释放mRNA到细胞质翻译机制；</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">2、增强免疫反应的辅助作用；</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">3、减少注射部位过度炎症或非靶反应引起的不良事件或毒性。</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">4、剂量</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">5、效力和递送效率</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">6、内小体释放</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">7、电荷和配体介导的靶向</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">8、脂质纳米颗粒的辅助作用</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">9、注射部位的反应、安全性、耐受性以及mRNA LNP的反应原性。</span></em></span></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t" style="color: rgb(51, 51, 51);font-size: 17px;text-align: justify;"><section data-mpa-template="t" mpa-from-tpl="t"><section mpa-from-tpl="t"><section style="margin-top: 10px;margin-bottom: 10px;text-align: center;font-size: 13px;text-indent: 0em;"><section mpa-from-tpl="t" style="padding-top: 0.5em;padding-right: 0.2em;display: inline-block;"><section mpa-from-tpl="t" style="padding: 3px;display: inline-block;vertical-align: top;width: 3em;height: 3em;border-color: rgb(16, 101, 230);border-style: solid;border-width: 1px;border-radius: 100%;"><section mpa-from-tpl="t" style="width: 30.5px;height: 31px;border-radius: 100%;background-color: rgb(16, 101, 230);color: rgb(255, 255, 255);font-size: 19px;line-height: 1.4;"><p style="clear: both;min-height: 1em;" mpa-is-content="t">八</p></section></section><section mpa-from-tpl="t" style="margin-left: -0.5em;display: inline-block;vertical-align: top;width: 6px;height: 6px;border-radius: 100%;background-color: rgb(16, 101, 230);"><br mpa-from-tpl="t"></section></section></section></section></section></section><section style="margin-top: 0.5em;margin-bottom: 0.5em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t" mpa-is-content="t">mRNA-LNP的设计简介</strong></section><section style="margin-top: 0.5em;margin-bottom: 1em;clear: both;min-height: 1em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t"></strong></section></section></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">一般情况下mRNA-LNP的设计要素包括：</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">（1）mRNA的序列设计和核苷酸的修饰选择；</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">（2）LNP的化学组成和配方优化，以达到包裹和递送mRNA的目的；</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">（3）长期保存。这三个要素需要做出具体的设计选择。</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">目前mRNA-LNP的设计成功否，通过以下几个方面进行评估：编码RNA的表达水平；基于胞内将mRNA视为外源因子而产生的免疫原性；LNP的化学组成的稳定性和毒性；包括给药途径、治疗目标都需要被测试。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">重要的是mRNA-LNP的系统性给药应区别于被普遍使用的肌肉给药。表达量、稳定性和生物毒性来对mRNA-LNP进行有效设计的最主要目的。</span></section><section><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">8.1 LNP 配方注意事项</span></h2></section></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">LNPs和mRNA载体都具有保护mRNA避免其在递送到靶细胞之前被降解的作用。通常情况下，LNP是一种脂质制剂，由不同比例的中性结构脂质、胆固醇、PEG-脂质和阳离子脂质组成。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(16, 101, 230);"><strong><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">8.1.1 阳离子脂质</span></strong></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">阳离子脂质被认为是最重要的组成成分，并以此来区分不同的mRNA-LNPs疫苗。阳离子脂质库正在被不断地筛选和扩充，只有那些能够增加表达量，同时提供良好免疫应答，又具备较低毒性的才被允许入库。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">阳离子脂质体的结构包括：可电离的头部；接头区域；烃链（如图）。尽管不同的阳离子脂质体千差万别，但用于mRNA-LNPs疫苗的阳离子脂质体具备一些基本的结构特点。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: center;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;"></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><strong><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">1） 可电离的头部基团</span></strong></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">mRNA-1273和BNT162b2疫苗各自包含不同的可电离脂质，但它们都含有一个氨基醇头基，pKa分别为6.75和6.09。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">Moderna的一项研究声称，在mRNA疫苗后引发适应性免疫反应的可电离脂质pKa的最佳范围是6.6-6.9，而6.2-6.6的pKa范围已被证明是IVT递送后蛋白质表达的最佳范围。有趣的是mRNA-1273可电离脂质的pKa与BNT162b2不一致，因为后者是6.09。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><strong><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">2）接头区域</span></strong></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">接头区域将头部基团与脂烃尾部连接起来，并对RNA-LNP体内活性产生影响。可以预测接头区域有助于头部基团pKa的保持和RNA-LNP（进入细胞前）逃逸潜力。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">且对接头区域优化的研究是一个持续的过程。阳离子脂质库正在被不断地筛选和扩充，以使其更有效地递送RNA-LNP。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><strong><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">3）烃链（脂质尾部）</span></strong></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">阳离子脂质的尾部结构，影响到了LNP结构，进而影响并改变体内逃逸、储存期间的稳定性和生物毒性，进而影响蛋白的表达效率。研究表明各种不饱和度和疏水尾的对称性与LNP的稳定性和有效性之间存在相关性。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">例如，支链烃类脂尾可能会产生更像是个锥形的结构，从而增强体内逃逸。而且通过引入酯键到脂质烃链以改善阳离子脂质体的药代动力学特性。FDA批准的第一个阳离子脂质体DLin-MC3-DMA(MC3)，它具备较长组织半衰期。这也推动了可生物降解阳离子脂质体的发展，以改善脂质代谢，避免毒性。可以在烃尾或者接头区域中引入一个或多个酯键，它们在体内酯酶作用下裂解，从而改善脂质的药代动力学特性，并降低毒性。</span></section><p style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">众多的研究正在不断试图寻找链中的最佳酯键位置。如果酯键放置得太靠近头部基团或者接头区域，就会降低头部基团pKa值，降低LNP效果。因此，最好将它们定位在脂质尾部的更加下游区域。目前，mRNA-1273和BNT162b2都含有带有可生物降解键的支链烃尾。</span></p><section><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">8.2 聚乙二醇（PEG）脂质</span></h2></section></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;line-height: 2em;text-indent: 0em;margin-bottom: 24px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">聚乙二醇脂质的占总成分的组成比一般小于2.5%。它提供LNP的自身稳定性和纳米颗粒大小的稳定，防止相互聚集，防止LNP的解聚。但是需要控制PEG的浓度，如果浓度高，它会阻止RNA进入细胞。</span></section><p style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;line-height: 2em;text-indent: 0em;margin-bottom: 0px;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">近来有很多关于PEG免疫反应的报道，需要寻求更安全的替代品，如多聚肌氨酸。其中mRNA-1273和BNT162b2的PEG占比分别为1.5和1.6%。</span></p><section><br></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><h2 mpa-is-content="t" style="margin: 25px 0px 5px;padding-right: 10px;padding-left: 10px;font-weight: bold;max-width: 100%;font-variant-numeric: normal;font-variant-east-asian: normal;letter-spacing: 0.544px;text-align: justify;white-space: normal;widows: 1;border-left: 5px solid rgb(16, 101, 230);line-height: 32px;background-color: rgb(255, 255, 255);border-top-color: rgb(16, 101, 230);border-bottom-color: rgb(16, 101, 230);border-right-color: rgb(16, 101, 230);text-indent: 0em;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="border-color: rgb(16, 101, 230);color: rgb(16, 101, 230);" mpa-is-content="t">8.3 长期保存</span></h2></section></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">mRNA-LNP疫苗的长期储存和稳定性是在配方设计中的一个主要考虑因素，并且目前尚未彻底解决。由于其高度的临床相关性和疫苗运输分装的过程，最终影响疫苗的价格。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">mRNA-1273作为第一个进入临床试验的SARS CoV-2 mRNA疫苗，发展速度令人惊讶。从病毒基因组的首次公布，他们用两天的时间完成了疫苗序列，用了25天完成了首剂制备，63天进入I期临床试验（NCT04283461）。但是达到全球疫苗供应，仍然存在一定的挑战。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">mRNA-LNP疫苗的超低温保存是一个重要需求。例如：BNT162b2需要-80℃，mRNA-1273需要-20℃。其原因在于mRNA-LNP疫苗在室温条件下不稳定，并且是由疫苗制备平台造成的。多项研究正在探索LNP冷冻条件。目前可以接受冻结LNP的冷冻保护剂有蔗糖或海藻糖，它们在mRNA-LNP制备后添加。赵博士研究了类脂质纳米颗粒（LLN）的长期储存条件，他们向储存在液氮中的LLNs mRNA制剂添加5%蔗糖或海藻糖，不但保留了颗粒的物理化学性质，并保持三个月的体内递送有效性。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">疫苗的冻干也可以成为一种选择，并且需要添加冻干保护剂。例如，Moderna的II期mRNA-LNP CMV疫苗(mRNA-1647)可以在5℃保持18个月的稳定性。不过冻干是一个昂贵且耗时的过程。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">稳定剂：蔗糖被允许使用在mRNA-1273和BNT162b中，在终产品中均含有10%的蔗糖。不过需要指出的是，他们的起始温度不尽相同。BNT162b2需要-60到-80℃，mRNA-1273需要-15到-20℃。基于稳定性数据，近期欧洲药品管理局(EMA)批准BNT162b2可以-15到-25℃维持两周。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">虽然关于分装和存储的限制可以通过设计温控运输容器，从工程角度来解决问题，但是关于冷冻的稳定特性仍然需求研究。近期有假设提出：冷冻的目的是保护LNP中的RNA，而并不主要是保护LNP本身的稳定性。随着时间的延长，LNP可能发生降解、融合和破裂。可以通过增加稳定作用的脂质来解决，例如PEG，毕竟RNA的断裂在此前尚未被研究。因此LNP的稳定性很重要，区别于短期非冰冻疫苗的限制性因素。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">LNP内的mRNA降解的快慢取决于存储时间和温度。它主要通过核酸磷酸二酯主链的水解而发生，水解可发生在酸性或碱性条件下。因为在研究之初，包裹较小的RNA时，如siRNA，阳离子脂质头朝内，内部几乎没有水，而避免了RNA的降解。但是最近的研究表明LNP包裹的mRNA包含在它们的核心可电离脂质、胆固醇和水。研究表明，高达24%的LNP核心是由水构成，这会影响LNP内的mRNA稳定性。这或许可以解释为什么FDA批准siRNA LNP (Patisiran)可在2到8℃下储存24个月。而当前的mRNA-LNP COVID疫苗可在此温度条件下保存一个月，且是未稀释的疫苗原液。</span></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t" style="color: rgb(51, 51, 51);font-size: 17px;text-align: justify;"><section data-mpa-template="t" mpa-from-tpl="t"><section mpa-from-tpl="t"><section style="margin-top: 10px;margin-bottom: 10px;text-align: center;font-size: 13px;text-indent: 0em;"><section mpa-from-tpl="t" style="padding-top: 0.5em;padding-right: 0.2em;display: inline-block;"><section mpa-from-tpl="t" style="padding: 3px;display: inline-block;vertical-align: top;width: 3em;height: 3em;border-color: rgb(16, 101, 230);border-style: solid;border-width: 1px;border-radius: 100%;"><section mpa-from-tpl="t" style="width: 30.5px;height: 31px;border-radius: 100%;background-color: rgb(16, 101, 230);color: rgb(255, 255, 255);font-size: 19px;line-height: 1.4;"><p style="clear: both;min-height: 1em;" mpa-is-content="t">九</p></section></section><section mpa-from-tpl="t" style="margin-left: -0.5em;display: inline-block;vertical-align: top;width: 6px;height: 6px;border-radius: 100%;background-color: rgb(16, 101, 230);"><br mpa-from-tpl="t"></section></section></section></section></section></section><section style="margin-top: 0.5em;margin-bottom: 0.5em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t" mpa-is-content="t">核酸递送脂质纳米颗粒国内发展的问题</strong></section><section style="margin-top: 0.5em;margin-bottom: 1em;clear: both;min-height: 1em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t"></strong></section></section></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">对于核酸药物，LNP与其他递送系统相比，其包封效果、体内外表达效果、体内安全性等多方面都更具优势，可以说脂质纳米颗粒（LNP）是最佳的递送系统。国内已有多家企业，例如：艾博生物，斯微生物，丽凡达生物等均投资研发核酸药物脂质纳米颗粒递送系统关键技术。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">目前有三大难题依然制约国内脂质纳米颗粒技术的发展：</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">1.辅料的缺乏，脂质纳米颗粒辅料的研发，辅料国产化；</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">2. 缺乏成熟的工业化生产设备；</span></em></span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="color: rgb(232, 22, 105);"><em><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;letter-spacing: 1px;">3.缺乏既懂得制剂学和高分子材料学，又懂得制药工程设备的人才；</span></em></span></section><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t"><section data-mpa-template="t" mpa-from-tpl="t" style="color: rgb(51, 51, 51);font-size: 17px;text-align: justify;"><section data-mpa-template="t" mpa-from-tpl="t"><section mpa-from-tpl="t"><section style="margin-top: 10px;margin-bottom: 10px;text-align: center;font-size: 13px;text-indent: 0em;"><section mpa-from-tpl="t" style="padding-top: 0.5em;padding-right: 0.2em;display: inline-block;"><section mpa-from-tpl="t" style="padding: 3px;display: inline-block;vertical-align: top;width: 3em;height: 3em;border-color: rgb(16, 101, 230);border-style: solid;border-width: 1px;border-radius: 100%;"><section mpa-from-tpl="t" style="width: 30.5px;height: 31px;border-radius: 100%;background-color: rgb(16, 101, 230);color: rgb(255, 255, 255);font-size: 19px;line-height: 1.4;"><p style="clear: both;min-height: 1em;" mpa-is-content="t">十</p></section></section><section mpa-from-tpl="t" style="margin-left: -0.5em;display: inline-block;vertical-align: top;width: 6px;height: 6px;border-radius: 100%;background-color: rgb(16, 101, 230);"><br mpa-from-tpl="t"></section></section></section></section></section></section><section style="margin-top: 0.5em;margin-bottom: 0.5em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t" mpa-is-content="t">小结</strong></section><section style="margin-top: 0.5em;margin-bottom: 1em;clear: both;min-height: 1em;color: rgb(51, 51, 51);font-size: 17px;text-align: center;text-indent: 0em;"><strong style="color: rgb(16, 101, 230);font-size: 16px;" mpa-from-tpl="t"></strong></section></section></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">有效的mRNA-LNP设计成功包含了多种考虑和选择，需要根据治疗目进行设计研究。虽然成功的mRNA LNP没有统一的配方，不过仍然有些共同的地方有迹可循。在RNA的序列、修饰和优化过程中，需要最大限度保证蛋白的表达。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">关于配方，目前现行的mRNA-LNP疫苗有相似的脂质体配比，阳离子脂质体和PEG脂质体又是多种多样的可供选择。虽然现行的两种疫苗中的阳离子脂质不相同，但是它们关于氨基醇头基和支链烃类脂尾在结构上相似地具有酯键。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">尽管研究一直在尝试增强mRNA-LNP 的蛋白质表达，但是蛋白质的高表达与适应性免疫应答的高效性之间的相关性很弱。筛选配方的终点应该是能够引发适应性免疫反应，而不是整体蛋白质的表达量。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">mRNA-LNP疫苗的稳定性和长期保存是非常重要的。关键点是LNP内的mRNA链稳定性和LNP载体稳定性。</span></section><section style="margin-top: 0pt;margin-left: 0pt;font-size: 12pt;font-family: Cambria;font-weight: normal;text-align: justify;margin-bottom: 24px;line-height: 2em;text-indent: 0em;"><span style="font-family: Helvetica Neue, Helvetica, Hiragino Sans GB, Microsoft YaHei, Arial, sans-serif;font-size: 15px;color: rgb(74, 75, 76);letter-spacing: 1px;">如上所述，脂质纳米颗粒LNP作为非常有前景的核酸药物载体，在制药行业已备受关注。特别是现在，LNP是mRNA疫苗的关键技术，在有效保护mRNA并将其运输到细胞当中发挥着举足轻重的作用。同时LNP也应用扩展到其他领域，比如医学影像、化妆品、营养品、农业以及纳米反应器等。随着新辅料的发现，制备工艺的创新改进，LNP会表现出更复杂的内部结构和更优的物理稳定性，未来将会看到更多基于LNP递送的核酸药物上市，为肿瘤等多种疾病提供治疗方案。</span></section><p><span style="font-size: 12px;color: rgb(149, 151, 153);">参考资料：</span></p><p><span style="font-size: 12px;color: rgb(149, 151, 153);">1、颇尔中国《mRNA-LNP浓缩换液工艺要点解析，一文了解！》</span></p><p><span style="font-size: 12px;color: rgb(149, 151, 153);">2、文章图片取自-<span style="font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-size: 12px;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;float: none;display: inline !important;">颇尔中国、瑞普利金</span></span></p><p><span style="font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, Helvetica Neue, PingFang SC, Hiragino Sans GB, Microsoft YaHei UI, Microsoft YaHei, Arial, sans-serif;font-style: normal;font-variant-ligatures: normal;font-variant-caps: normal;font-weight: 400;letter-spacing: normal;orphans: 2;text-align: justify;text-indent: 0px;text-transform: none;widows: 2;word-spacing: 0px;-webkit-text-stroke-width: 0px;text-decoration-thickness: initial;text-decoration-style: initial;text-decoration-color: initial;float: none;font-size: 12px;color: rgb(149, 151, 153);display: inline !important;">3、其他公开资料</span></p>
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