Development of Mannosylated Lipid Nanoparticles for mRNA Cancer Vaccine with High Antigen Presentation Efficiency and Immunomodulatory Capability

• Published in: Angewandte Chemie International Edition Vol. 63; no. 13; pp. e202318515 - n/a
• Main Authors: Lei, Jiaqi, Qi, Shaolong, Yu, Xinyang, Gao, Xiaomin, Yang, Kai, Zhang, Xueyan, Cheng, Meiqi, Bai, Bing, Feng, Yunxuan, Lu, Meixin, Wang, Yangfan, Li, Hongjian, Yu, Guocan
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 22.03.2024; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Anticancer properties; Antigen presentation; Antigen-presenting cells; Antigens; Antitumor activity; Antitumour agents; Cancer; Cancer immunotherapy; Cancer vaccines; CD45 antigen; Chemistry; Chemistry, Multidisciplinary; Cytotoxicity; Dendritic cell targeting; Dendritic cells; Down-regulation; Effectiveness; Endocytosis; Immune checkpoint blockade; Immune checkpoint inhibitors; Immunomodulation; Injection; Lipid nanoparticles; Lipids; Lymphocytes; Lymphocytes T; Mannose; mRNA; mRNA vaccine; mRNA vaccines; Nanoparticles; Physical Sciences; Science & Technology; Side effects; Vaccines; Immune checkpoint blockade; Dendritic cell targeting; TOLERANCE; MANNOSE; Cancer immunotherapy; UP-REGULATION; DOMAINS; Lipid nanoparticles; mRNA vaccine; DELIVERY
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202318515

Insufficient accumulation of lipid nanoparticles (LNPs)‐based mRNA vaccines in antigen presenting cells remains a key barrier to eliciting potent antitumor immune responses. Herein, we develop dendritic cells (DCs) targeting LNPs by taking advantage of mannose receptor‐mediated endocytosis. Efficient delivery of mRNA to DCs is achieved in vitro and in vivo utilizing the sweet LNPs (STLNPs‐Man). Intramuscular injection of mRNA vaccine (STLNPs‐Man@mRNAOVA) results in a four‐fold higher uptake by DCs in comparison with commercially used LNPs. Benefiting from its DCs targeting ability, STLNPs‐Man@mRNAOVA significantly promotes the antitumor performances, showing a comparable therapeutic efficacy by using one‐fifth of the injection dosage as the vaccine prepared from normal LNPs, thus remarkably avoiding the side effects brought by conventional mRNA vaccines. More intriguingly, STLNPs‐Man@mRNAOVA exhibits the ability to downregulate the expression of cytotoxic T‐lymphocyte‐associated protein 4 on T cells due to the blockade of CD206/CD45 axis, showing brilliant potentials in promoting antitumor efficacy combined with immune checkpoint blockade therapy. In order to promote the antitumor efficacy of mRNA vaccines, sweet lipid nanoparticles (STLNPs‐Man) are developed by incorporating a mannosylated ionizable lipid to enhance the uptake by DCs through the mannose receptor‐mediated endocytosis. Interestingly, STLNPs‐Man exhibits the ability to downregulate the expression of cytotoxic T‐lymphocyte‐associated protein 4 on T cells through the blockade of CD206/CD45 axis to further potentiate the antitumor immunity.