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Article(id=1210148018163159285, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210148010437243088, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-0363, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1648396800000, receivedDateStr=2022-03-28, revisedDate=1651075200000, revisedDateStr=2022-04-28, acceptedDate=null, acceptedDateStr=null, onlineDate=1766451370992, onlineDateStr=2025-12-23, pubDate=1660233600000, pubDateStr=2022-08-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766451370992, onlineIssueDateStr=2025-12-23, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766451370992, creator=13701087609, updateTime=1766451370992, updator=13701087609, issue=Issue{id=1210148010437243088, tenantId=1146029695717560320, journalId=1189982191388893191, year='2022', volume='57', issue='8', pageStart='2245', pageEnd='2556', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766451369151, creator=13701087609, updateTime=1766451533022, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1210148697808179705, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210148010437243088, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1210148697808179706, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210148010437243088, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2327, endPage=2333, ext={EN=ArticleExt(id=1210148018616144129, articleId=1210148018163159285, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Research progress of nano delivery system in mRNA tumor vaccines, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Tumor vaccine is one of the most promising therapeutic strategies in tumor immunotherapy. It promotes the antigen presentation process by delivering tumor antigen and then activates the anti-tumor immune response. As a new class of vaccines, messenger RNA (mRNA) vaccines can activate the immune system to achieve the purpose of immunotherapy by delivering the mRNA sequence of a specific antigen into the body and expressing the corresponding antigen protein. Compared with traditional vaccines, mRNA vaccines have the advantages of a short production cycle, high effectiveness, and strong immunogenicity. In recent years, the application of mRNA vaccines in tumor immunotherapy has attracted widespread attention, but the instability and low delivery efficiency of mRNA limit its application. Nano delivery system can effectively solve the problem of mRNA vaccine delivery, greatly promote the research process and clinical application of mRNA tumor vaccines, and has become a hot spot in the research of mRNA vaccines. In this review, we introduced the mRNA tumor vaccines, focusing on the application of nano delivery system in mRNA tumor vaccines, in order to provide new ideas and new methods for the efficient delivery of mRNA tumor vaccines and tumor immunotherapy.

, correspAuthors=Yong-jun LIU, Na ZHANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2022 Acta Pharmaceutica Sinica. All rights reserved., 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=Pan-pan GU, Tong GAO, Yong-jun LIU, Na ZHANG), CN=ArticleExt(id=1210148019455004965, articleId=1210148018163159285, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=纳米递送系统在mRNA肿瘤疫苗中的研究进展, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

肿瘤疫苗是肿瘤免疫治疗中极具发展前景的治疗策略之一, 其通过递送肿瘤抗原促进抗原递呈过程, 进而激活抗肿瘤免疫反应。信使RNA (messenger RNA, mRNA) 疫苗是一种新型疫苗, 通过向体内递送特定抗原的mRNA序列并表达相应抗原蛋白, 从而激活机体免疫系统达到免疫治疗的目的。mRNA疫苗与传统疫苗相比具有生产周期短、有效性高和免疫原性强等优势, 近年来mRNA疫苗在肿瘤免疫治疗中的应用引起广泛关注, 但mRNA的不稳定性和低递送效率限制了其应用。纳米递送系统能有效解决mRNA疫苗递送的难题, 极大地促进mRNA肿瘤疫苗的研究进程和临床应用, 已成为mRNA疫苗研究的热点。本文对mRNA肿瘤疫苗进行介绍, 重点对纳米递送系统在mRNA肿瘤疫苗中的应用进行综述, 以期为mRNA肿瘤疫苗高效递送及肿瘤免疫治疗提供新思路和新方法。

, correspAuthors=刘永军, 张娜, authorNote=null, correspAuthorsNote=
*刘永军, Tel: 86-531-88382589, E-mail: ;
张娜, Fax: 86-531-88382548, E-mail:
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Acta Pharmacol Sin, 2020, 41: 959-969., articleTitle=Ex vivo pulsed dendritic cell vaccination against cancer, refAbstract=null), Reference(id=1210148032759337081, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, doi=10.1016/j.jconrel.2019.08.002, pmid=null, pmcid=null, year=2019, volume=310, issue=null, pageStart=36, pageEnd=46, url=null, language=null, rfNumber=[45], rfOrder=44, authorNames=null, journalName=J Control Release, refType=null, unstructuredReference=Tateshita N, Miura N, Tanaka H, et al. Development of a lipoplex-type mRNA carrier composed of an ionizable lipid with a vitamin E scaffold and the KALA peptide for use as an ex vivo dendritic cell-based cancer vaccine[J]. J Control Release, 2019, 310: 36-46., articleTitle=Development of a lipoplex-type mRNA carrier composed of an ionizable lipid with a vitamin E scaffold and the KALA peptide for use as an ex vivo dendritic cell-based cancer vaccine, refAbstract=null)], funds=[Fund(id=1210148025830347401, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, awardId=82173757, language=CN, fundingSource=国家自然科学基金资助项目(82173757), fundOrder=null, country=null), Fund(id=1210148025964565142, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, awardId=82173756, language=CN, fundingSource=国家自然科学基金资助项目(82173756), fundOrder=null, country=null), Fund(id=1210148026069422750, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, awardId=2017WLJH40, language=CN, fundingSource=山东大学青年学者未来计划(2017WLJH40), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1210148019744411954, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, xref=null, ext=[AuthorCompanyExt(id=1210148019756994868, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, companyId=1210148019744411954, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China), AuthorCompanyExt(id=1210148019769577782, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, companyId=1210148019744411954, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=山东大学药学院, 天然产物化学生物学教育部重点实验室, 山东 济南 250012)])], figs=[ArticleFig(id=1210148023565423108, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, language=EN, label=null, caption=null, figureFileSmall=zHgKC+pNv399YrEY4VNGkw==, figureFileBig=U/nyCRxxdp8Hqi0iMyWy0w==, tableContent=null), ArticleFig(id=1210148023670280716, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, language=CN, label=Figure 1, caption= Nano delivery system of messenger RNA (mRNA) tumor vaccines. 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The translated antigen protein can stimulate the immune system and achieve immunotherapy , figureFileSmall=HbPL8NaPgVR55LPpagI1bw==, figureFileBig=6TzCXUItgyZS0PxsRRBSkw==, tableContent=null), ArticleFig(id=1210148024173597260, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Type of nanocarriermRNA encoding sequenceTarget tissue/cellType of cancerRef.
LPXOVA and gp70DCTumor[12]
LPXE7DCHPV16-positive malignancies[13]
LNPgp100, TRP2 and OVADC, macrophage and neutrophilMelanoma[14]
CLPPCK19TumorLung cancer[15]
CPPOVADC–[16]
CD-PEIOVADCTumor[17]
LPPOVA, E7DCCervical carcinoma[18]
LPPTRP2DCMelanoma[19]
Cationic lipid-assisted nanoparticlesOVADCLymphoma[20]
MSNOVADCLymphoma[21]
GO-PEIOVALNMelanoma[22]
), ArticleFig(id=1210148025431888479, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, language=CN, label=Table 1, caption=

Nano delivery system of mRNA tumor vaccines. LPX: Lipoplex; E7: The human papillomavirus 16 oncoprotein E7; CK19: Cytokeratin 19; OVA: Ovalbumin; DC: Dendritic cells; HPV: Human papilloma virus; TRP2: Tyrosinase related protein-2; LNP: Lipid nanoparticle; CLPP: A protamine/liposome system; CPP: Cell-penetrating peptide; CD-PEI: Cyclodextrin-polyethyleneimine; GO-PEI: Graphene oxide-polyethyleneimine; MSN: Mesoporous silica; LN: Lymph node

, figureFileSmall=null, figureFileBig=null, tableContent=
Type of nanocarriermRNA encoding sequenceTarget tissue/cellType of cancerRef.
LPXOVA and gp70DCTumor[12]
LPXE7DCHPV16-positive malignancies[13]
LNPgp100, TRP2 and OVADC, macrophage and neutrophilMelanoma[14]
CLPPCK19TumorLung cancer[15]
CPPOVADC–[16]
CD-PEIOVADCTumor[17]
LPPOVA, E7DCCervical carcinoma[18]
LPPTRP2DCMelanoma[19]
Cationic lipid-assisted nanoparticlesOVADCLymphoma[20]
MSNOVADCLymphoma[21]
GO-PEIOVALNMelanoma[22]
), ArticleFig(id=1210148025566106220, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
mRNA encoding sequenceVehicleRoute of administrationType of cancerNCT number/phase
NY-ESO-1, MAGE-A3, Tyr and TPTERNA-LPXIntravenous injectionMelanomaNCT04526899/phase Ⅱ
E6 and E7RNA-LPXIntravenous injectionHead and neck cancerNCT04534205/phase Ⅱ
5 Antigens expressed in de novo and metastatic
prostate cancer		LiposomeIntravenous injectionProstate cancerNCT04382898/phase I
and Ⅱ
TriMix and 5 tumor associated antigens mRNALNPIntranodal injectionMelanomaNCT03394937/phase I
OX40L, IL-23 and IL-36γLNPIntratumoral injectionSolid tumor malignancies and
lymphoma		NCT03739931/phase I
mRNA-4157: Neo-AgLNPIntramuscular injectionSolid tumorsNCT03313778/phase I
NY-ESO-1, MAGE-C1, MAGE-C2, survivin,
5T4 and MUC-1		ProtamineIntradermal injectionNSCLCNCT03164772/phase I
and Ⅱ
PSA, PSCA, PSMA, STEAP1ProtamineIntradermal injectionProstate cancerNCT00831467/phase I
and Ⅱ
Neo-AgLPPSubcutaneous injectionEsophageal cancer and NSCLCNCT03908671/phase I
), ArticleFig(id=1210148025662575224, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148018163159285, language=CN, label=Table 2, caption=

Clinical trial of mRNA vaccines for tumor immunotherapy. NY-ESO-1: New York esophageal squamous cell carcinoma 1; Tyr: Tyrosinase; MAGE: Melanoma-associated antigen; TPTE: Transmembrane phosphatase with tensin homology; RNA-LPX: Liposomal antigen-encoding RNA; OX40L: OX40 ligand; IL: Interleukin; PSA: Prostate specific antigen; PSCA: Prostate stem cell antigen; PSMA: Prostate specific membrane antigen; STEAP1: Six-segment transmembrane epithelial antigen of prostate 1; NSCLC: Non-small cell lung cancer; Neo-Ag: Neoantigen

, figureFileSmall=null, figureFileBig=null, tableContent=
mRNA encoding sequenceVehicleRoute of administrationType of cancerNCT number/phase
NY-ESO-1, MAGE-A3, Tyr and TPTERNA-LPXIntravenous injectionMelanomaNCT04526899/phase Ⅱ
E6 and E7RNA-LPXIntravenous injectionHead and neck cancerNCT04534205/phase Ⅱ
5 Antigens expressed in de novo and metastatic
prostate cancer		LiposomeIntravenous injectionProstate cancerNCT04382898/phase I
and Ⅱ
TriMix and 5 tumor associated antigens mRNALNPIntranodal injectionMelanomaNCT03394937/phase I
OX40L, IL-23 and IL-36γLNPIntratumoral injectionSolid tumor malignancies and
lymphoma		NCT03739931/phase I
mRNA-4157: Neo-AgLNPIntramuscular injectionSolid tumorsNCT03313778/phase I
NY-ESO-1, MAGE-C1, MAGE-C2, survivin,
5T4 and MUC-1		ProtamineIntradermal injectionNSCLCNCT03164772/phase I
and Ⅱ
PSA, PSCA, PSMA, STEAP1ProtamineIntradermal injectionProstate cancerNCT00831467/phase I
and Ⅱ
Neo-AgLPPSubcutaneous injectionEsophageal cancer and NSCLCNCT03908671/phase I
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纳米递送系统在mRNA肿瘤疫苗中的研究进展
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顾盼盼 , 高彤 , 刘永军 * , 张娜 *
药学学报 | 综述 2022,57(8): 2327-2333
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药学学报 | 综述 2022, 57(8): 2327-2333
纳米递送系统在mRNA肿瘤疫苗中的研究进展
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顾盼盼, 高彤, 刘永军* , 张娜*
作者信息
  • 山东大学药学院, 天然产物化学生物学教育部重点实验室, 山东 济南 250012

通讯作者:

*刘永军, Tel: 86-531-88382589, E-mail: ;
张娜, Fax: 86-531-88382548, E-mail:
Research progress of nano delivery system in mRNA tumor vaccines
Pan-pan GU, Tong GAO, Yong-jun LIU* , Na ZHANG*
Affiliations
  • Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
出版时间: 2022-08-12 doi: 10.16438/j.0513-4870.2022-0363
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摘要
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肿瘤疫苗是肿瘤免疫治疗中极具发展前景的治疗策略之一, 其通过递送肿瘤抗原促进抗原递呈过程, 进而激活抗肿瘤免疫反应。信使RNA (messenger RNA, mRNA) 疫苗是一种新型疫苗, 通过向体内递送特定抗原的mRNA序列并表达相应抗原蛋白, 从而激活机体免疫系统达到免疫治疗的目的。mRNA疫苗与传统疫苗相比具有生产周期短、有效性高和免疫原性强等优势, 近年来mRNA疫苗在肿瘤免疫治疗中的应用引起广泛关注, 但mRNA的不稳定性和低递送效率限制了其应用。纳米递送系统能有效解决mRNA疫苗递送的难题, 极大地促进mRNA肿瘤疫苗的研究进程和临床应用, 已成为mRNA疫苗研究的热点。本文对mRNA肿瘤疫苗进行介绍, 重点对纳米递送系统在mRNA肿瘤疫苗中的应用进行综述, 以期为mRNA肿瘤疫苗高效递送及肿瘤免疫治疗提供新思路和新方法。

mRNA疫苗  /  肿瘤疫苗  /  纳米递送系统  /  肿瘤治疗  /  免疫治疗

Tumor vaccine is one of the most promising therapeutic strategies in tumor immunotherapy. It promotes the antigen presentation process by delivering tumor antigen and then activates the anti-tumor immune response. As a new class of vaccines, messenger RNA (mRNA) vaccines can activate the immune system to achieve the purpose of immunotherapy by delivering the mRNA sequence of a specific antigen into the body and expressing the corresponding antigen protein. Compared with traditional vaccines, mRNA vaccines have the advantages of a short production cycle, high effectiveness, and strong immunogenicity. In recent years, the application of mRNA vaccines in tumor immunotherapy has attracted widespread attention, but the instability and low delivery efficiency of mRNA limit its application. Nano delivery system can effectively solve the problem of mRNA vaccine delivery, greatly promote the research process and clinical application of mRNA tumor vaccines, and has become a hot spot in the research of mRNA vaccines. In this review, we introduced the mRNA tumor vaccines, focusing on the application of nano delivery system in mRNA tumor vaccines, in order to provide new ideas and new methods for the efficient delivery of mRNA tumor vaccines and tumor immunotherapy.

mRNA vaccine  /  tumor vaccine  /  nano delivery system  /  tumor treatment  /  immunotherapy
顾盼盼, 高彤, 刘永军, 张娜. 纳米递送系统在mRNA肿瘤疫苗中的研究进展. 药学学报, 2022 , 57 (8) : 2327 -2333 . DOI: 10.16438/j.0513-4870.2022-0363
Pan-pan GU, Tong GAO, Yong-jun LIU, Na ZHANG. Research progress of nano delivery system in mRNA tumor vaccines[J]. Acta Pharmaceutica Sinica, 2022 , 57 (8) : 2327 -2333 . DOI: 10.16438/j.0513-4870.2022-0363
正文
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信使RNA (messenger RNA, mRNA) 疫苗是指在体外合成编码特定抗原的mRNA序列, 通过特定的递送系统递送至体内并表达相应抗原蛋白, 从而刺激机体产生特异性免疫反应以达到免疫治疗目的的免疫制剂。1990年, Wolff等[1]将mRNA通过肌内注射到小鼠骨骼肌后, 发现在小鼠体内表达出相应的蛋白, 首次揭示mRNA技术在疫苗研究领域应用的可能性。1995年, Conry等[2]构建了编码荧光素酶和人癌胚抗原的mRNA剪切体, 通过注射以脂质体为载体的mRNA后小鼠获得抗肿瘤免疫反应, 首次探讨并提出将接种mRNA疫苗作为肿瘤治疗的手段。在肿瘤治疗领域, mRNA疫苗也从多种类型疫苗中脱颖而出, 研究发展较为迅速。与DNA相比, mRNA具有如下优势: 安全性更高, 无需入细胞核即可表达, 没有感染或癌变风险[3]; 效率更高, 可通过序列优化和各种载体修饰途径提高mRNA的翻译效率和稳定性; 制备更快, 针对任意序列已知的目标蛋白, 可在短时间内合成其mRNA, 节省药物研发时间[4]。mRNA肿瘤疫苗逐渐受到研究者青睐, 也拓宽了个性化疫苗开发的道路。
尽管mRNA疫苗具有非常广阔的应用前景, 但仍存在如下障碍: ① mRNA不稳定, 易被核酸酶降解而难以有效内化; ②尺寸大, 携带的负电荷多, 递送效率低[5]。纳米递送系统能有效压缩mRNA, 避免其在递送过程中被酶降解[6]; 通过在载体表面修饰甘露糖或抗CD40抗体等, 能将mRNA高效靶向递送到淋巴器官如淋巴结(lymph node, LN)[7]或抗原递呈细胞(antigen-presenting cell, APC), 从而增加抗原摄取和呈递, 提高疫苗效率; 被内吞后可诱导溶酶体逃逸, 提高mRNA的抗原蛋白转染效率。纳米递送系统已成为mRNA肿瘤疫苗的研究热点。
1 mRNA肿瘤疫苗
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mRNA分为非复制型mRNA (nonreplicating mRNA, NRM) 和自扩增型mRNA (self-amplifying mRNA, SAM) 两类。NRM是用线性的质粒DNA或聚合酶链式反应模板通过体外转录合成, 其结构简单、RNA序列较短且没有额外编码蛋白。SAM是将编码抗原的序列直接插入单链RNA病毒中, 其中目的基因替换编码结构蛋白的基因, 而编码mRNA复制的基因是完整的[8]。SAM能产生更高的抗原表达水平并可持续表达, 然而SAM的分子质量远大于NRM, 导致其生产过程比NRM复杂。此外, SAM中额外编码蛋白如复制酶的免疫原性难以控制, 可能会诱导非预期的免疫反应, 其安全性尚待考证[9]。
mRNA肿瘤疫苗一般是使用编码肿瘤源性抗原的mRNA, 通过人体蛋白质合成系统翻译出特异性肿瘤抗原蛋白作为“靶标”, 诱导机体产生针对“靶标”的免疫应答, 进而识别并清除肿瘤细胞。目前疫苗编码的肿瘤源性抗原主要有肿瘤相关抗原(tumor associated antigen, TAA) 和新生抗原(neoantigen, Neo-Ag)。此外, 一些mRNA疫苗也可编码免疫刺激物如细胞因子、趋化因子等用于肿瘤治疗[10]。与其他类型肿瘤疫苗相比, mRNA肿瘤疫苗生产工艺简单, 制备速度更快, 易于批量生产; 有效性高, 具有双重免疫机制, 免疫原性强; 研发周期短, 能快速开发新型候选疫苗用于肿瘤精准和个性化的治疗。
此外, mRNA不仅能编码抗原, 还能在某些情况下提供佐剂活性, 通过激活Toll样受体(Toll-like receptor, TLR), 如TLR3、TLR7和TLR8等, 提供共刺激信号促进树突状细胞(dendritic cell, DC) 成熟, 增强免疫反应强度[11]。
2 mRNA肿瘤疫苗的纳米递送系统
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由于mRNA自身稳定性和递送效率的限制, 开发高效靶向递送系统是mRNA疫苗亟待解决的问题。在mRNA疫苗研究中, 已提出许多递送策略, 其中非病毒载体中的纳米递送系统制备简单、免疫原性较低, 并可促进抗原和佐剂共递送, 已成为mRNA递送的首选载体(图 1、表 1[12-22])。
2.1 基于脂质的纳米载体
脂质纳米粒(lipid nanoparticle, LNP) 是一种生物相容性载体, 核心空腔可实现对mRNA的负载, 其制备方式有挤压法、超声法、均质法等, 最近微流控技术已成功用于LNP的制备和尺寸控制[23]。LNP的制备和mRNA的装载过程相对简易, 已作为非病毒递送载体被广泛研究[24], 目前Pfizer-BioNTech和Moderna公司开发的两款广泛使用的mRNA新冠疫苗即以LNP为载体[25]。LNP脂质壳结构主要由胆固醇、中性磷脂、聚乙二醇(polyethylene glycol, PEG)-脂质和可电离脂质组成[26], 都发挥各自作用以保证载体的递送功能。其中, 胆固醇稳定LNP; 中性磷脂支持脂质双层结构并有助于溶酶体逃逸[27]; PEG-脂质能延长疫苗的半衰期, 防止颗粒聚集; 可电离脂质在酸性条件下带正电, 能通过静电作用吸附负电性的mRNA形成复合物, 是mRNA递送和转染效率的决定性因素[28]。
可电离脂质是LNP中的关键成分, 根据结构特性可分为不饱和型、多尾型、聚合物型、可生物降解型和支化型脂质。可电离脂质的结构改变可引起mRNA递送效率的改变[29]。如Miao等[30]将炔烃和酯基引入脂质尾部以修饰4-(N, N-二甲基氨基)丁酸(二亚油基)甲酯(Dlin-MC3-DMA) 的主链结构, 通过优化筛选, 表明炔烃可电离脂质能显著提高mRNA递送效率。Liu等[31]设计出包括1个两性离子头和3个尾部的多尾型可电离脂质, 优化的脂质易于插入膜磷脂中, 能诱导相变促进mRNA的释放, 提高其递送效率。
此外, 还可通过改善LNP配方得到最优的mRNA递送效果。Oberli等[14]通过比较几种不同脂质的组合, 得到了最佳配方B11, 然后用编码肿瘤抗原酪氨酸酶相关蛋白2 (tyrosinase related protein-2, TRP2) 和100 kDa糖蛋白(gp100) 的mRNA制备B11 LNP, 对携带B16F10黑色素瘤的小鼠进行治疗性疫苗接种, 结果显示肿瘤萎缩并有效延长小鼠的总体生存率。LNP凭借其各方面的独特优势, 已成为目前研究较多、应用前景最广的纳米载体系统。
2.2 基于蛋白/多肽的纳米载体
蛋白/多肽具有相对稳定性、低免疫原性和低毒性, 也可作为mRNA递送系统。其中阳离子鱼精蛋白可压缩并保护mRNA, 但鱼精蛋白和mRNA之间相互作用过于紧密, 单独使用鱼精蛋白-mRNA复合物会降低疫苗有效性。CureVac公司的研究者开发了利用鱼精蛋白复合物和裸mRNA的混合物来提高疫苗免疫刺激效果的RNActive®技术, 将裸露的mRNA和鱼精蛋白-mRNA复合物以1∶1比例制备并用于肿瘤治疗, 其中鱼精蛋白-mRNA复合物仅作为佐剂, 裸露的mRNA用于抗原生产[32]。此外, 阳离子细胞穿透肽(cell-penetrating peptide, CPP) 具有较低的电荷密度和优异的膜破坏能力, 也能负载mRNA。如Udhayakumar等[16]采用含有两亲性RALA基序的CPP将mRNA压缩成纳米复合物, 该复合物显示出pH依赖性膜破坏特性, 能有效刺激DC摄取mRNA并促进CD8+ T细胞增殖。
目前针对基因药物使用较多的是阳离子脂质体, 但单独使用脂质体时其体内递送效率有限, 而阳离子蛋白多肽能高效浓缩mRNA[33]形成纳米递送系统并防止溶酶体或核酸酶降解, 因此常将二者联合应用于递送。Lei等[34]设计了鱼精蛋白/脂质体系统(CLPP), 通过鱼精蛋白将mRNA浓缩成纳米级, 实现纳米药物递送系统的有效构建。CLPP递送mRNA能保护其不被核酸酶降解、转染效率高且稳定性较好。
2.3 基于聚合物的纳米载体
阳离子聚合物在结构改性和开发方面具有良好的灵活性, 可通过静电吸附作用压缩负电性的mRNA, 避免其被核酸酶降解, 提高递送效率。目前应用较多的阳离子聚合物有聚乙烯亚胺(polyethyleneimine, PEI)、聚(β-氨基酯)[poly(β-amino esters), PBAE]、壳聚糖等, 大多用于mRNA递送的聚合物材料需修饰以提高其转染效率和稳定性[35]。Tan等[17]开发了一种由β-环糊精(β-cyclodextrin, β-CD) 修饰支化聚乙烯亚胺(bPEI) 组成的PEI衍生物(CP), 实验结果显示CP-mRNA复合物的体外转染效率远高于bPEI-mRNA复合物。此外, 可生物降解的PBAE在mRNA递送方面表现出色。Capasso Palmiero等[36]通过连接己内酯单元配制各种PBAE三元共聚物, 其中最稳定的三元共聚物表现出比PEI更高的转染效率, 为PBAE载体静脉递送mRNA以进行疫苗接种和癌症免疫治疗提供可能。
其次, 聚合物和脂质也常联合用于mRNA递送。脂质多聚复合物(lipoployplex, LPP) 是将mRNA分子包载到聚合物核心中, 然后将核心加载到磷脂双分子层壳中得到多聚复合物。以卵清蛋白(ovalbumin, OVA) 为代表的模型抗原是目前应用最为广泛的模型抗原之一, Persano等[37]开发了以PBAE/mOVA (编码OVA的mRNA) 为核心, 包裹在脂质壳中组成的LPP/mRNA疫苗, 该疫苗能刺激DC成熟并呈递抗原, 具有强大的抗肿瘤活性。此外, 除了单独递送mRNA外, 佐剂与mRNA共递送能达到更强的肿瘤治疗效果。Guevara等[19]设计了基于佐剂α-半乳糖基神经酰胺和TRP2-mRNA共递送的LPP载体, 得到的mRNA疫苗显著增强了抗原特异性CD8+ T细胞的增殖, 同时增加Th1细胞介导的免疫应答。
2.4 基于无机材料的纳米载体
无机纳米粒(inorganic nanoparticles, INP) 是一种多功能纳米平台, 具有优越的固有理化性质和性能, 作为核酸载体也展示了良好的递送效率。最常见的INP是介孔硅纳米粒(mesoporous silica, MSN), 其具有有序的介孔结构, 生物相容性好, 能有效携带并递送mRNA。Zhang等[21]开发了由裸mRNA和双链RNA依赖的蛋白质激酶(PKR) 抑制剂C16组成的MSN-mRNA皮下递送系统(C6@MSN), 并在E.G7-OVA肿瘤模型上应用该疫苗制剂, 结果显示, 该疫苗产生了有效的肿瘤抑制, 表明MSN-mRNA递送系统在肿瘤治疗中具有巨大的转化潜力。
无机材料和聚合物联合用于mRNA的递送, 可实现高效递送和压缩核酸的功能。Yin等[22]用氧化石墨烯(graphene oxide, GO) 和PEI构建了可注射水凝胶, 通过π-π堆积和静电作用封装mOVA和佐剂R848。该水凝胶经皮下注射后, 可转化为含有mOVA和R848的纳米疫苗, 保护mRNA不被降解并靶向LN, 从而显著增加抗原特异性CD8+ T细胞的数量并产生持久的抗肿瘤免疫。
此外, 无机材料和脂质体也可联合使用作为mRNA疫苗递送的载体。Liu等[38]开发了具有不对称脂质双层涂层的磷酸钙纳米粒(LCP), 其内部包载编码mucin 1黏蛋白的mRNA (MUC1-mRNA), 表面修饰甘露糖。甘露糖能靶向LN中DC上的甘露糖受体, 使LCP成功地将MUC1-mRNA高效递送到LN中的DC处。LCP通过与抗细胞毒性T淋巴细胞相关蛋白4抗体联用, 能诱导强烈的抗原特异性细胞毒性T淋巴细胞(cytotoxic T lymphocyte, CTL) 反应, 实现三阴性乳腺癌免疫治疗。
3 纳米递送系统在mRNA肿瘤疫苗的应用
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mRNA肿瘤疫苗需将相关转录本(即在体外合成的编码特定抗原的mRNA序列) 递送至APC (主要为DC) 中, 以表达相应的抗原蛋白, 抗原蛋白经主要组织相容性复合体(MHC) 即MHC-Ⅰ或MHC-Ⅱ递呈给CD8+和CD4+ T细胞, 继而启动适应性免疫应答, 达到抗肿瘤作用(图 2)。将mRNA导入DC是肿瘤疫苗制备的重要步骤, 根据mRNA转染DC的位置(体内、外), 目前临床上主要有两种针对肿瘤治疗的mRNA疫苗: ① mRNA纳米载体疫苗: 通过构建载体包载mRNA得到疫苗并直接注射, 使其在体内激活DC[39]; ②联合DC的mRNA纳米载体疫苗: 从患者外周血分离单核细胞, 在体外诱导分化成DC, 然后将载有mRNA的纳米载体转染至DC, 再回输至患者体内发挥抗肿瘤作用[40]。通过对新的疫苗纳米递送载体和对机体免疫系统作用机制的不断深入研究, 目前已有多项mRNA疫苗进入肿瘤治疗的临床试验。
3.1 mRNA纳米载体疫苗
利用载体(脂质体、LNP等) 压缩mRNA得到mRNA疫苗是目前肿瘤疫苗研发焦点。Miao等[41]开发了一系列LNP介导mRNA递送, 并通过刺激干扰素基因途径(STING) 提供靶向免疫刺激, 从而提高了对小鼠黑色素瘤的疫苗效力。因具有良好的稳定性、高转染效率和安全性, 多种mRNA载体疫苗已进入临床研究(表 2)。mRNA-4157是Moderna公司开发的为患者量身定做的个性化癌症疫苗, 可编码34种Neo-Ag, 其递送载体为LNP。Ⅰ期临床试验结果显示, 在所有测试剂量下, 患者均具有良好耐受性, 并引发了Neo-Ag特异性T细胞反应[42]。目前mRNA-4157已进入Ⅱ期临床试验阶段, 与单独使用pembrolizumab相比, 使用mRNA-4157和pembrolizumab联合治疗的疗效(NCT03897881), 结果显示黑色素瘤患者的无复发生存期长达3年, 令人鼓舞。
BNT111是BioNTech公司研发的一款编码NY-ESO-1、酪氨酸酶(tyrosinase, Tyr)、MAGE-A3和TPTE这4种TAA的mRNA疫苗, 通过RNA-LPX静脉注射递送至患者体内, Ⅰ期临床单药剂量递增试验中期分析结果表明, BNT111能诱导特异性抗肿瘤免疫应答, 且安全性和耐受性良好[43]。目前BioNTech公司正在Ⅱ期临床评估联合使用BNT111和cemiplimab的疗效(NCT04526899), 与单独使用BNT111或cemiplimab相比, 黑色素瘤患者的客观缓解率达到24个月, 显示出良好的临床疗效。
除了以LNP和RNA-LPX为载体, CureVac公司开发的BI1361849 (原名CV9202) 采用鱼精蛋白递送编码6种非小细胞肺癌(non-small cell lung cancer, NSCLC) 相关抗原的mRNA, 目前BI1361849处于Ⅰ/Ⅱ期临床试验阶段(NCT03164772)。
3.2 联合DC的mRNA纳米载体疫苗
与纳米载体直接递送mRNA相比, DC不仅能装载递送mRNA, 还能作为APC呈递肿瘤抗原, 诱导免疫应答。从患者外周血中分离单核细胞后在体外培养, 然后经粒细胞-巨噬细胞集落刺激因子、白细胞介素-4诱导下刺激分化为未成熟DC[44], 成熟DC可通过内吞作用将mRNA纳米载体内化, 最后通过不同的给药途径回输到体内, 由此制备的疫苗用于肿瘤治疗即为联合DC的mRNA纳米载体肿瘤疫苗。Tateshita等[45]开发了一种脂质复合物型mRNA载体用于DC疫苗, 该载体使用SS可切割和pH激活的类脂物质(ssPalm-LNP) 和KALA肽组合而成(ssPalm-KALA), 将载有mOVA的ssPalm-KALA转染至小鼠骨髓来源DC后回输至体内, 结果显示该疫苗能在小鼠体内诱导OVA特异性CTL活性, 继而产生显著的抗肿瘤作用。DC具有高mRNA转染效率、安全性和有效性, 然而疫苗需激活大量DC, 制备工艺较为复杂, 既耗时又费力, 且目前更多采用电穿孔等方法直接将mRNA转染至DC, 因此联合DC的mRNA纳米载体疫苗应用很少。
4 总结与展望
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随着mRNA疫苗纳米递送系统的发展, 越来越多的研究将其应用在肿瘤免疫治疗领域并取得了较好疗效。2021年11月19日, BioNTech公司的mRNA肿瘤疫苗BNT111 (NCT04526899) 获得快速通道资格, 表明mRNA疫苗在临床肿瘤治疗中的良好应用前景。但是, mRNA疫苗在动物模型和人体内递送和肿瘤杀伤能力等方面仍有差异, 还需进一步探索和完善; 此外, 疫苗的最佳给药途径、接种剂量和次数也是临床研究的重要方向。相信随着mRNA疫苗和纳米材料研究的不断深入, mRNA肿瘤疫苗纳米递送系统将会为肿瘤免疫治疗翻开新的篇章。
作者贡献: 顾盼盼负责文献查阅、文章撰写; 高彤负责提供思路并编排文章; 刘永军和张娜负责确定文章选题及指导写作, 并对文章撰写质量进行把关和审校。
利益冲突: 本文不存在任何与本稿件相关的利益冲突。
基金
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  • 国家自然科学基金资助项目(82173757)
  • 国家自然科学基金资助项目(82173756)
  • 山东大学青年学者未来计划(2017WLJH40)
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2022年第57卷第8期
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doi: 10.16438/j.0513-4870.2022-0363
  • 接收时间：2022-03-28
  • 首发时间：2025-12-23
  • 出版时间：2022-08-12
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  • 收稿日期：2022-03-28
  • 修回日期：2022-04-28
基金
国家自然科学基金资助项目(82173757)
国家自然科学基金资助项目(82173756)
山东大学青年学者未来计划(2017WLJH40)
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    山东大学药学院, 天然产物化学生物学教育部重点实验室, 山东 济南 250012

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*刘永军, Tel: 86-531-88382589, E-mail: ;
张娜, Fax: 86-531-88382548, E-mail:
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Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
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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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