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Article(id=1236731778380133049, tenantId=1146029695717560320, journalId=1235980733773295621, issueId=1236731777142804746, articleNumber=null, orderNo=null, doi=10.20251/j.cnki.1003-3734.2025.17.004, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=null, receivedDateStr=null, revisedDate=null, revisedDateStr=null, acceptedDate=1744819200000, acceptedDateStr=2025-04-17, onlineDate=1772789433331, onlineDateStr=2026-03-06, pubDate=1757865600000, pubDateStr=2025-09-15, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1772789433331, onlineIssueDateStr=2026-03-06, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1772789433331, creator=13701087609, updateTime=1772789433331, updator=13701087609, issue=Issue{id=1236731777142804746, tenantId=1146029695717560320, journalId=1235980733773295621, year='2025', volume='34', issue='17', pageStart='1793', pageEnd='1904', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=1, specialIssue=0, createTime=1772789433036, creator=13701087609, updateTime=1772801868692, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1236783936152596961, tenantId=1146029695717560320, journalId=1235980733773295621, issueId=1236731777142804746, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1236783936152596962, tenantId=1146029695717560320, journalId=1235980733773295621, issueId=1236731777142804746, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1814, endPage=1819, ext={EN=ArticleExt(id=1236731778631791291, articleId=1236731778380133049, tenantId=1146029695717560320, journalId=1235980733773295621, language=EN, title=Advances in non-clinical safety evaluation of mRNA drug delivery carriers, columnId=null, journalTitle=Chinese Journal of New Drugs, columnName=null, runingTitle=null, highlight=null, articleAbstract=

Since the outbreak of the coronavirus epidemic, how to deal with sudden large-scale infectious diseases has become a global research hotspot. The first mRNA vaccine BNT162b2, which was urgently approved by the US FDA, has shown good efficacy in dealing with the novel coronavirus. It not only provides new solutions for sudden infectious diseases but has also attracted widespread attention in the field of drug research and development. However, the molecular structure of mRNA is unstable, and needs to be delivered to the target site with the support of carriers to exert its efficacy. The composition of mRNA drug delivery carrier is complex and is the main factor causing adverse drug reactions, which may lead to different types of adverse drug reactions, such as immune responses and inflammatory reaction. This paper mainly discusses the potential safety risks in mRNA drug-related carriers, as well as the consideration points and reference cases in non-clinical safety evaluation, so as to provide references for exploring and building scientific safety evaluation methods for mRNA drugs.

, correspAuthors=Ying HUANG, Xing-chao GENG, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Yi-kun ZHANG, Tian-tian HOU, Zi-yi JIN, Ying HUANG, Xing-chao GENG), CN=ArticleExt(id=1236731779093164736, articleId=1236731778380133049, tenantId=1146029695717560320, journalId=1235980733773295621, language=CN, title=mRNA药物载体非临床安全性评价研究进展, columnId=1236330553964810454, journalTitle=中国新药杂志, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

如何应对突发性大规模传染疾病已成为全球范围内的研究热点，美国FDA紧急批准上市的首款mRNA疫苗BNT162b2对新型冠状病毒展现出了良好的疗效，不仅为突发性传染病提供新的解决思路，在药物研发领域也引起了广泛关注。然而，mRNA分子结构不稳定，需要借助载体才能进入目标靶位发挥药效。mRNA药物递送载体成分复杂，是引起药物不良反应的主要因素，可能会引发不同类型的不良反应，如免疫反应、炎症反应等。本文主要探讨mRNA药物相关载体中潜在的安全性风险，以及在非临床安全评价中的考虑要点和参考案例，为探索和构建mRNA药物的科学的安全性评价方法提供参考。

, correspAuthors=黄瑛, 耿兴超, authorNote=null, correspAuthorsNote=
*黄瑛，女，副研究员，博士，主要从事药物毒理研究。联系电话：（010）67876252，E-mail:
耿兴超，男，研究员，博士，主要从事药物毒理研究。联系电话：（010）67872233，E-mail: 。
, copyrightStatement=null, copyrightOwner=《中国新药杂志》有限公司, extLink=null, articleAbsUrl=null, sourceXml=T75SJAhxL/W+ApIMV5+Q4Q==, magXml=fzo6xDw9QycH91dDb8X6DA==, pdfUrl=null, pdf=q0yLFJeQ2pfaKIqoB26CiA==, pdfFileSize=866193, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=UOJkR8irWmwN/Qtcjbo/Ng==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=6USRsN+J/NEaTuhZa1CUUg==, mapNumber=null, authorCompany=null, fund=null, authors=

张屹坤，男，硕士研究生，研究方向：药物安全性评价。E-mail: 。

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张屹坤，男，硕士研究生，研究方向：药物安全性评价。E-mail: 。

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商品名适应证公司机构上市日期
mRESVIA呼吸道合胞体病毒感染Moderna公司2022-01
Spikevax新冠病毒感染Moderna公司2024-05
度恩泰新冠病毒感染石药集团2023-03
AWcorna新冠病毒感染艾博生物/沃森生物公司2022-09
沃蓝安安新冠病毒感染沃森生物公司2023-12
斯维尔克新冠病毒感染斯微（上海）生物科技股份有限公司2022-12
Kostaive新冠病毒感染Arcturus Therapeutics Holdings公司2025-02
Daichirona新冠病毒感染第一三共株式会社2023-08
Bimervax新冠病毒感染Laboratorios HIPRA SA公司2023-03
复必泰新冠病毒感染BioNTech公司/Pfizer公司2021-08
智克威得新冠病毒感染安徽智飞龙科马生物制药有限公司2023-02
众爱可维新冠病毒感染北京生物制品研究所有限责任公司2021-08
克尔来福新冠病毒感染北京科兴中维生物技术有限公司2022-01
众康可维新冠病毒感染武汉生物制品研究所有限责任公司2022-02
克威莎新冠病毒感染康希诺生物股份公司2022-02
), ArticleFig(id=1236792932653658877, tenantId=1146029695717560320, journalId=1235980733773295621, articleId=1236731778380133049, language=CN, label=表1, caption=

mRNA上市药物信息

, figureFileSmall=null, figureFileBig=null, tableContent=
商品名适应证公司机构上市日期
mRESVIA呼吸道合胞体病毒感染Moderna公司2022-01
Spikevax新冠病毒感染Moderna公司2024-05
度恩泰新冠病毒感染石药集团2023-03
AWcorna新冠病毒感染艾博生物/沃森生物公司2022-09
沃蓝安安新冠病毒感染沃森生物公司2023-12
斯维尔克新冠病毒感染斯微（上海）生物科技股份有限公司2022-12
Kostaive新冠病毒感染Arcturus Therapeutics Holdings公司2025-02
Daichirona新冠病毒感染第一三共株式会社2023-08
Bimervax新冠病毒感染Laboratorios HIPRA SA公司2023-03
复必泰新冠病毒感染BioNTech公司/Pfizer公司2021-08
智克威得新冠病毒感染安徽智飞龙科马生物制药有限公司2023-02
众爱可维新冠病毒感染北京生物制品研究所有限责任公司2021-08
克尔来福新冠病毒感染北京科兴中维生物技术有限公司2022-01
众康可维新冠病毒感染武汉生物制品研究所有限责任公司2022-02
克威莎新冠病毒感染康希诺生物股份公司2022-02
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mRNA药物载体非临床安全性评价研究进展
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张屹坤 , 侯田田 , 金紫怡 , 黄瑛 * , 耿兴超 *
中国新药杂志 | 综述 2025,34(17): 1814-1819
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中国新药杂志 | 综述 2025, 34(17): 1814-1819
mRNA药物载体非临床安全性评价研究进展
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张屹坤 , 侯田田, 金紫怡, 黄瑛* , 耿兴超*
作者信息
  • 中国食品药品检定研究院国家药物安全评价监测中心、细胞及基因治疗药物质量和非临床研究与评价北京市重点实验室，北京　100176

    • 张屹坤，男，硕士研究生，研究方向：药物安全性评价。E-mail: 。

通讯作者:

*黄瑛，女，副研究员，博士，主要从事药物毒理研究。联系电话：（010）67876252，E-mail:
耿兴超，男，研究员，博士，主要从事药物毒理研究。联系电话：（010）67872233，E-mail: 。
Advances in non-clinical safety evaluation of mRNA drug delivery carriers
Yi-kun ZHANG , Tian-tian HOU, Zi-yi JIN, Ying HUANG* , Xing-chao GENG*
Affiliations
  • National Center for Safety evaluation of Drugs, National Institutes for Food and Drug Control, Beijing Key Laboratory of Quality Control and Non-clinical Research and Evaluation for Cellular and Gene Therapy Medicinal Products, Beijing 100176, China
出版时间: 2025-09-15 doi: 10.20251/j.cnki.1003-3734.2025.17.004
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摘要
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如何应对突发性大规模传染疾病已成为全球范围内的研究热点，美国FDA紧急批准上市的首款mRNA疫苗BNT162b2对新型冠状病毒展现出了良好的疗效，不仅为突发性传染病提供新的解决思路，在药物研发领域也引起了广泛关注。然而，mRNA分子结构不稳定，需要借助载体才能进入目标靶位发挥药效。mRNA药物递送载体成分复杂，是引起药物不良反应的主要因素，可能会引发不同类型的不良反应，如免疫反应、炎症反应等。本文主要探讨mRNA药物相关载体中潜在的安全性风险，以及在非临床安全评价中的考虑要点和参考案例，为探索和构建mRNA药物的科学的安全性评价方法提供参考。

mRNA药物  /  载体  /  毒性  /  非临床安全评价  /  不良反应

Since the outbreak of the coronavirus epidemic, how to deal with sudden large-scale infectious diseases has become a global research hotspot. The first mRNA vaccine BNT162b2, which was urgently approved by the US FDA, has shown good efficacy in dealing with the novel coronavirus. It not only provides new solutions for sudden infectious diseases but has also attracted widespread attention in the field of drug research and development. However, the molecular structure of mRNA is unstable, and needs to be delivered to the target site with the support of carriers to exert its efficacy. The composition of mRNA drug delivery carrier is complex and is the main factor causing adverse drug reactions, which may lead to different types of adverse drug reactions, such as immune responses and inflammatory reaction. This paper mainly discusses the potential safety risks in mRNA drug-related carriers, as well as the consideration points and reference cases in non-clinical safety evaluation, so as to provide references for exploring and building scientific safety evaluation methods for mRNA drugs.

mRNA drug  /  carrier  /  toxicity  /  non-clinical safety evaluation  /  adverse reaction
张屹坤, 侯田田, 金紫怡, 黄瑛, 耿兴超. mRNA药物载体非临床安全性评价研究进展. 中国新药杂志, 2025 , 34 (17) : 1814 -1819 . DOI: 10.20251/j.cnki.1003-3734.2025.17.004
Yi-kun ZHANG, Tian-tian HOU, Zi-yi JIN, Ying HUANG, Xing-chao GENG. Advances in non-clinical safety evaluation of mRNA drug delivery carriers[J]. Chinese Journal of New Drugs, 2025 , 34 (17) : 1814 -1819 . DOI: 10.20251/j.cnki.1003-3734.2025.17.004
正文
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mRNA药物是一类通过递送系统将编码好的外源mRNA递送进入细胞内部，并由宿主翻译系统表达特定功能蛋白，从而实现预防疾病或治疗作用的生物制剂。作为一类极具前景的新型药物，mRNA药物相较于传统药物的优势有以下几点：①药物研发周期短，能够快速响应突发性疫情。②安全性高，在载体的辅助下，mRNA药物于细胞质发挥功能，不会整合进入宿主基因组[1]。③mRNA药物产物为蛋白质，能够通过生物代谢途径被完全降解[1]。④mRNA疫苗具有佐剂效应，能够有效提高机体免疫应答能力，进一步增强机体免疫力[2]。mRNA药物由mRNA分子与纳米载体构成，mRNA分子包含5′端帽结构、3′端帽结构与Poly（A）尾、开放阅读框（open reading frame，ORF）及其周围的5′非翻译区（5′untranslated region,5′UTR）和3′非翻译区（3′untranslated region, 3′UTR）构成。两端的帽子结构和Poly（A）尾能够影响mRNA的稳定性和翻译效率[3]，5′UTRs和3′UTRs能够提高药物表达水平、翻译效率和半衰期[4]，见图1。mRNA分子为天然产物，对机体产生的毒性较小，主要的毒性由药物载体引起，mRNA药物递送载体目前主要为脂质纳米颗粒（lipid nanoparticles, LNPs），在研的递送载体有无机纳米颗粒载体、外泌体、病毒样纳米颗粒载体等。迄今为止，共有15款mRNA药物获批上市（见表1），其中包括美国FDA批准的疫苗：辉瑞和BioNTech联合研发的首个新型冠状病毒（以下简称“新冠病毒”）疫苗复必泰，以及由Moderna研发的新冠病毒疫苗Spikevax和首个非新冠病毒适应证疫苗mRESVIA等。在中国，国家药品监督管理局批准了中国石药集团有限公司、中国斯微生物科技股份有限公司和中国艾博生物等研发的新冠病毒疫苗共8款产品。
mRNA药物作为近年来药物研发领域的热点之一，有许多药物处于临床前研发阶段，药物在临床前的安全性评价数据相对有限。本文通过深入探讨不同载体系统的潜在毒性、作用机制并对载体的安全性评价方法进行了系统梳理，为探索和建立适用于mRNA药物的安全性评价科学方法提供参考。
1　潜在安全性风险
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1.1　LNPs载体的毒性风险
1.1.1　不良免疫效应
LNPs由辅助脂质、胆固醇、聚乙二醇化脂质（PEGylated lipids, PEGs）、可电离的阳离子脂质混合而成[5]。辅助脂质和胆固醇具有结构支撑和稳定作用，PEGs会促进LNPs的稳定性，可电离的阳离子脂质能与带负电荷的mRNA分子结合，促进mRNA分子从内核体转入细胞质中，进而与核糖体结合，翻译出相关蛋白质[6]。PEGs是LNPs中引起免疫相关不良反应的主要成分[7]，其具有免疫原性，会导致一种补体相关的类过敏反应（CARPA）。PEG化药物会导致患者体内抗PEG的IgM和IgG上升，这些抗药抗体会中和药物，降低药物的临床疗效。此外，由PEG化药物产生的抗药性抗体，会加速药物的血液清除，导致疗效降低和超敏反应或迟发型超敏反应[8]，甚至过敏性休克和死亡。mRNA疫苗tozinameran和CX-024414是欧盟使用的2种新冠病毒疫苗，接种疫苗的部分患者出现心肌炎或心包炎[9]，研究发现每100万例接种疫苗CX-024414的患者出现心肌炎的概率为17.27例，出现心包炎的概率为9.76例；每100万例接种tozinameran疫苗的患者发现心肌炎的概率为8.44例，出现心包炎的概率为5.79例。有观点认为是疫苗接种后引起炎症发生所致的不良反应[10]，还有观点认为疫苗接种的强效免疫原性RNA可能对心脏有旁观者效应或辅助作用[11]。
1.1.2　炎症反应
在mRNA药物Spikevax的评估报告中提到mRNA-LNP疫苗肌肉注射后可在脑内检测到极低水平的mRNA，这预示着mRNA-LNP复合物能够跨越血脑屏障，到达神经系统，但未检测到神经系统不良反应。mRNA-LNP疫苗会引起强大的体液免疫反应，导致接种部位产生急性炎症不良反应，如疼痛、肿胀、发热等[12]，可能与阳离子脂质引起的炎性反应有关。阳离子脂质的炎症反应表现为肌肉疼痛、头疼和高热[13]，这可能与阳离子脂质诱导以补体激活和细胞因子IFN-γ, TNF-α, IL-6, IL-12诱导为特征的强烈的炎性反应有关[14]。
1.1.3　其他不良反应
阳离子脂质引起的不良反应主要包括细胞毒性、炎症反应、肝毒性、白细胞减少、血小板减少等[15]。阳离子脂质表面具有高密度的正电荷，会导致大量的活性氧（ROS）生成[16]，ROS诱导细胞毒性和细胞凋亡[17]，降低细胞膜的稳定性，影响细胞膜上的离子通道与信号传导系统[18]。阳离子脂质还能够进入细胞内部，与细胞器膜相互作用，影响膜的完整性和功能，进而影响细胞的正常的生理功能。阳离子脂质的肝毒性主要表现为血清转氨酶升高，如谷丙转氨酶和谷草转氨酶。库普弗细胞会吞噬脂质复合物，是LNPs在肝中蓄积的主要原因[13]。血液学检查表现为白细胞减少和血小板减少。
1.2　外泌体纳米颗粒载体的毒性风险
外泌体是细胞分泌的传递信息的纳米级囊泡[19]，其直径在40～160 nm之间，因其具有良好的耐受性和生物相容性和较低的免疫原性[20]，被认为是一种极具前景的纳米药物递送载体。外泌体作为药物载体使用，已经用于免疫系统疾病、肾损伤疾病、癌症等多种疾病的药物治疗研究。需对其安全性进行评估，外泌体可能具有神经毒性和生殖毒性风险，作为纳米颗粒载体，其纳米尺寸可能使其具有穿透血脑屏障的能力，从而引发神经毒性[21]。免疫原性也是外泌体可能存在的毒性风险，外泌体的组分复杂，经过特殊靶向修饰后可能导致免疫原性和免疫毒性。
1.3　无机纳米颗粒载体的毒性风险
1.3.1　肝脏和肾脏毒性
无机纳米颗粒是一种稳定性高、生物相容性良好、不良反应小的新型药物载体，种类丰富，包含有银纳米颗粒、金纳米颗粒、氧化铁纳米颗粒等。无机纳米颗粒对人体重要器官可能存在潜在的风险，包括肝脏、肾脏[22]、大脑、睾丸和心脏[23]。研究表明，金属纳米颗粒会在肝脏中蓄积，会导致肝毒性，损害肝功能[24]，还会诱导肝脏的氧化应激和炎症，进而导致肝损伤。肾脏也会受纳米颗粒诱导产生肾毒性、肾脏炎症和功能障碍[25]。纳米颗粒所导致的毒性可能与多种细胞超微结构改变有关，包括线粒体、内质网、溶酶体、质膜、高尔基体和细胞核[26]。金属纳米颗粒毒性的产生与线粒体超微结构的改变有关，因为线粒体是ATP生成、凋亡调节、ROS清除以及与其他细胞器相互作用的主要场所，承担着维持细胞功能的重要作用。Jarrar等[27]研究表明，银纳米颗粒可以诱导肝脏细胞线粒体超微结构发生改变，如肝细胞线粒体呈多形性、基质透明和嵴断裂。纳米银颗粒也会导致肾脏细胞超微结构变化，如近曲小管细胞刷状缘微绒毛密集。金纳米颗粒会导致肝细胞线粒体损伤，表现为肿胀、透亮基质和膜破裂，对肾脏的影响为肾脏远曲小管细胞出现线粒体肿胀、嵴溶解、偶见线粒体膜破裂。线粒体超微结构的改变表明线粒体渗透压和线粒体膜的完整性发生改变，进而影响到线粒体的功能。无机纳米颗粒会通过氧化应激、免疫系统激活和大分子相互作用等不同机制诱导线粒体损伤。
1.3.2　遗传毒性
无机纳米颗粒产生生物毒性的因素有多种，如物理损伤、生物相互作用等。因为无机纳米颗粒的粒径较小，易于浸润细胞内部，对细胞膜结构产生破坏，进入胞质中的无机纳米颗粒主要存在于胞质中，会干扰细胞的代谢功能，甚至引发细胞凋亡或坏死。纳米颗粒还会产生ROS自由基，导致氧化应激和炎症反应，进一步加剧细胞损伤。
1.4　病毒样颗粒（virus-like particles, VLPs）载体的毒性风险
VLPs是一种复杂的多聚体，具有能够进行自组装的蛋白质结构，直径为20～200 nm，病毒样颗粒与天然病毒的形态相似但不包含亲代病原体的物质，mRNA与VLPs上的衣壳蛋白特异性结合即可形成VLP-mRNA复合物，由于复合物粒径较小，易于进入细胞内部发挥药效。VLPs常见的局部不良反应有注射部位疼痛、肿胀，该不良反应与VLPs刺激机体所产生强烈的炎症反应相关[28]。全身不良反应有疲劳、胃肠系统症状和头痛。
1.5　其他纳米颗粒载体的毒性风险
仿生纳米颗粒载体的组成结构为功能性纳米颗粒和细胞膜涂层，通过携带有化疗药物、基因药物的功能性纳米颗粒发挥药效，细胞膜涂层有红细胞、白细胞等，起到递送、保护和靶向作用。虽然仿生纳米颗粒载体具有诸多优势，但其制备技术不完善，潜在毒性研究不全面，仍需对其进行全面的安全性评估。
聚合物纳米颗粒载体的构成结构为阳离子聚合物、树枝状聚合物或多糖聚合物，具有生物相容性好、可降解等特点。mRNA分子在静电吸引和疏水相互作用的帮助下与阳离子聚合物形成较为稳定的多聚体[29]。仿生纳米颗粒具有较好的生物相容性，较低的免疫原性，作为mRNA药物递送载体极具潜力，但其制备工艺复杂，应充分考虑其潜在的不良反应。
2　mRNA药物载体临床前评价研究
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对于mRNA药物载体的临床前安全性评估应充分考虑其在生物体内的分布、组织器官的蓄积以及对免疫系统的影响。
2.1　生物分布
mRNA药物载体的生物分布研究是评估药物安全性的重要环节，对于探究其对不同组织、器官的影响有着重要的意义。常用的生物分布研究技术有荧光素酶标记法、同位素标记法、定量聚合酶链反应（qPCR）和分支链DNA信号放大技术（bDNA）。荧光素酶标记法通过将编码荧光素酶的LNP注射入小鼠体内，通过活体成像技术可以实时监测其在小鼠内的分布过程。BioNTech公司/Pfizer公司研发的新冠病毒疫苗BNT162b2采用活体成像法检测mRNA在体内的分布，通过将包裹荧光素酶mRNA的LNP注射入小鼠体内进行生物分布研究，给药后6 h在注射部位和肝脏中均检测到荧光，48 h后肝脏中无法检测到荧光表达。LNP常通过同位素标记法进行体内分布研究，采用放射性[3H]标记LNP，该脂质标记物不会和细胞脂质交换，也不会被代谢。疫苗BNT162b2的LNP通过同位素试验进行分布检测，研究发现给药后在注射部位、血浆和大部分组织内均可检测到放射性，主要分布在肝脏、肾上腺、脾脏和卵巢。分支链DNA信号放大技术也是评估药物在体内分布的重要工具，取给药后小鼠各组织器官，采用bDNA法检测mRNA药物的含量，与活体成像技术相结合能够较为全面地分析药物在各组织器官的含量。Moderna公司研发的新冠病毒疫苗mRNA-1273采用bDNA法进行生物分布研究，给药后2 h在大鼠的脑、心脏、肺脏、眼球、睾丸等组织均检测到了mRNA分布。
2.2　免疫原性和免疫毒性
mRNA药物载体的免疫原性是其安全性评价中的另一个关键因素。由于mRNA药物载体中阳离子脂质和PEG化脂质具有免疫原性，能够引起细胞免疫与体液免疫，过强的免疫反应可能会产生免疫毒性，因此对其进行免疫原性的评估对于预测免疫相关不良反应有着重要的作用。常用的检测药物免疫原性的试验有抗药抗体检测、血液T细胞淋巴亚群分布等。常用的试验技术为酶联免疫吸附试验（Elisa）、流式细胞术。Nicolas Vabret团队采用流式细胞术评估T细胞免疫效应，研究人员在接种mRNA疫苗小鼠的外周血和脾脏样本中检测到了CD8+ T细胞，表明了该疫苗能够诱导T细胞免疫应答[30]。
2.3　一般毒性
mRNA药物的一般毒性检查主要为重复给药毒性实验。试验检查项目包含临床症状观察、注射部位观察、体重、摄食量、眼科学、血液学、尿液分析、凝血功能、组织病理学检测等，对于非人灵长类动物还可检测其体温、血压、心电图等指标。疫苗BNT162b2的临床前安全性评估研究中[31]，试验采取重复给药的方式，每周给雄性和雌性Wistar Han大鼠肌肉注射疫苗1次，共3剂，剂量设置为30和100 μg。该研究检测了体重、体温、注射部位、视力、听觉、血液学、凝血功能等指标，研究发现接种疫苗后24 h内大鼠平均体重较轻，恢复阶段对体重无明显影响；给药后4和24 h大鼠的体温较高；注射部位可观察到局部反应，出现轻微的红斑与水肿，且呈剂量依赖性；血液学检测结果显示白细胞升高，包含中性粒细胞、单核细胞、嗜酸性粒细胞、嗜碱性粒细胞；组织病理学结果显示脾脏重量增加、其余器官无明显变化。Ndeupen等[32]研究表明，肌肉注射mRNA药物会导致注射部位产生局部炎症如水肿及红斑，该不良反应主要为LNP中阳离子脂质固有炎症特性导致。当mRNA药物进入循环系统递送至全身时会产生各种不良反应，最为常见的是疼痛、肿胀、发热，这些不良反应主要是由IL-1β和IL-6等促炎细胞因子介导的炎症级联反应。因此，在其他种属动物体内进行阳离子脂质的促炎作用研究，深入解析其促炎作用通路，对LNP载体优化、推动药物临床转化具有重要指导意义。
3　结语
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目前，mRNA药物在应对突发性传染性疾病、治疗肿瘤等领域取得了重大进展，展现出极高的发展和应用潜力。相较于传统药物，mRNA药物的核心优势在于研发周期短，能够迅速应对新型病原体；药物安全性较高，不会整合进入基因，通过在细胞质内合成功能蛋白发挥疗效。但mRNA药物仍存在安全性风险，特别是mRNA药物递送系统中的成分，如PEGs、阳离子脂质、无机离子等，可能会导致炎症、肝肾损伤、过敏等不良反应。尚未有全面、系统和公认的mRNA药物的评价技术体系，现有的评价技术和方法不能够准确反映mRNA药物在体内的真实情况，对于药物的分布、代谢、潜在毒性效应等关键信息需要进行进一步挖掘。相信随着科学技术的不断进步和对mRNA药物载体毒性机制研究的深入，未来将构建出一套科学系统的评价体系，实现对mRNA药物进行全面的安全性评估，推动mRNA药物临床转化应用。
基金
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  • 国家重点研发计划课题(2024YFA1107302)
  • 药品监管科学全国重点实验室课题(2023SKLDRS0125)
文献
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2025年第34卷第17期
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doi: 10.20251/j.cnki.1003-3734.2025.17.004
  • 首发时间：2026-03-06
  • 出版时间：2025-09-15
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  • 录用日期：2025-04-17
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国家重点研发计划课题(2024YFA1107302)
药品监管科学全国重点实验室课题(2023SKLDRS0125)
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    中国食品药品检定研究院国家药物安全评价监测中心、细胞及基因治疗药物质量和非临床研究与评价北京市重点实验室，北京　100176

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*黄瑛，女，副研究员，博士，主要从事药物毒理研究。联系电话：（010）67876252，E-mail:
耿兴超，男，研究员，博士，主要从事药物毒理研究。联系电话：（010）67872233，E-mail: 。
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https://castjournals.cast.org.cn/joweb/zgxyzz/CN/10.20251/j.cnki.1003-3734.2025.17.004
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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