mRNA lipid nanoparticle cancer vaccine platform delivering multiple STING activators for enhanced antitumor activity

• 成果类型: Article
• 署名作者: Zeng, Ye; Xu, Junchao; Wang, Jinjin; Xue, Lulu; Liu, Jiageng; Geisler, Hannah C.; Ma, Xu; Melamed, Jilian R.; Shi, Qiangqiang; Padilla, Marshall S.; Luo, Zhangyi; Zhu, Jingcheng; Thatte, Ajay S.; Figueroa-Espada, Christian G.; Ang, Melgious Jin Yan; Murray, Amanda M.; Yamagata, Hannah M.; Kim, Dongyoon; Metzloff, Ann E.; Weissman, Drew; Mitchell, Michael J.
• 署名单位: University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Chinese Academy of Sciences; National Center for Nanoscience & Technology, CAS; Key Laboratory for Biological Effects of Nanomaterials & Nanosafety, CAS; Agency for Science Technology & Research (A*STAR); A*STAR - Bioprocessing Technology Institute (BTI); University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2525718123
• 发表日期: 2026-07-14
• 页码: e2525718123
• 关键词: nanoparticle; mRNA; cancer; immunotherapy; dendritic cells; DISCOVERY; PATHWAY

摘要

mRNA-based cancer vaccines offer a modular and safe platform to elicit antitumor immunity, yet their efficacy is often limited by inefficient mRNA delivery and inadequate dendritic cell (DC) activation, both of which are essential for initiating robust cytotoxic T cell responses. Inadequate innate immune activation coupled with poor antigen presentation further diminishes their effectiveness, particularly in immunologically cold tumors. While stimulator of interferon genes (STING) agonists can enhance DC maturation and cross-presentation, their therapeutic utility is constrained by poor intracellular delivery and limited colocalization with tumor antigens. In this study, we developed a lipid nanoparticle (LNP) platform via high-throughput screening of ionizable lipids for potent mRNA delivery to DCs both in vitro and in vivo. To amplify immune activation, we coencapsulated the STING agonists c-di-AMP (AMP) and manganese (Mn2+) together with tumor antigen-encoding mRNA into the lead LNP formulation. This codelivery strategy synergistically activated type I interferon signaling, upregulated costimulatory molecules, enhanced antigen presentation, and elicited potent tumor-specific T cell responses and superior antitumor efficacy. Our results demonstrate that integrating innate immune stimulation with mRNA-LNP delivery provides a promising strategy to overcome current limitations in mRNA vaccine efficacy and to improve cancer immunotherapy outcomes.