H1 - Engineered Apoptotic Mimicry Nanoparticles Boost mRNA Cancer Vaccine Efficacy and Induce Long-Lived Memory T Cells by Suppressing Inflammation

Introduction: : The success of messenger RNA (mRNA) vaccines using lipid nanoparticles (LNPs) has opened new possibilities for cancer immunotherapy. However, conventional LNP mRNA vaccines lack cell specificity, particularly for dendritic cells (DCs), which are crucial for eliciting antitumor immunity. They also activate innate immunity, including the type I interferon (IFN) signaling pathway, which can inhibit mRNA translation and reduce vaccine efficacy. Excessive type I IFN further skews T cell differentiation toward short-lived effector cells rather than memory precursors. To address these challenges, we developed a phosphatidylserine (PS)-containing LNP (PS-LNP) based on a viral apoptotic mimicry strategy, designed to enhance DC-specific tropism, suppress inflammation, and inhibit type I IFN responses.

Materials and

Methods: : A PS-LNP was designed to encapsulate mRNA encoding a reporter gene, a model antigen, or a tumor-specific neoantigen. In vitro studies using mouse bone marrow-derived dendritic cells (BMDCs) evaluated mRNA delivery, antigen presentation, T cell priming, and transcriptomic changes. In vivo evaluations included the assessment of DC tropism, mRNA expression, and immunological responses, as well as reactogenicity and inflammatory responses including type I IFN production. Antitumor efficacy was assessed following immunization with PS-LNP-formulated mRNA vaccines in both an ovalbumin (OVA)-expressing B16F10 melanoma model and an OVA-negative MC38 colon carcinoma model.

Results, Conclusions, and Discussions:: Compared to the conventional LNP formulation used in Spikevax (Moderna), PS-LNP exhibited enhanced DC tropism, improved endosomal escape, and greater mRNA expression and antigen presentation. These properties led to stronger CD8⁺ T cell priming and promoted the generation of antigen-specific memory precursor effector cells (MPECs) in vitro. Transcriptomic analysis confirmed reduced activation of inflammation-related pathways, particularly the type I IFN signaling pathway, suggesting improved mRNA translation efficiency. In addition, reduced type I IFN production was directly validated using an IFN-β luciferase reporter mouse model, supporting the inflammation-mitigating profile of PS-LNP in vivo. PS-LNP also decreased LNP-induced reactogenicity, including rectal temperature drop, neutrophil infiltration at the injection site, and the production of proinflammatory cytokines. Notably, PS-LNP significantly improved tumor therapeutic efficacy in both B16F10-OVA and MC38 models. It markedly increased antigen-specific CD8+ T cells and promoted the generation of MPECs, contributing to enhanced longevity and polyfunctionality of the T cell response.
This study shows that an engineered PS-based LNP employing viral apoptotic mimicry can enhance mRNA cancer vaccine efficacy by promoting DC targeting, mitigating inflammation, including type I IFN responses, and improving the magnitude and quality of CD8⁺ T cell responses. This platform holds promise as a versatile vaccine delivery system applicable to diseases beyond cancer.

Acknowledgements and/or References (Optional):: This work was supported by NIH (R01AI127070, R01CA210273, U01CA210152, R01DK108901, R01DE026728, R01DE030691, R01DE031951 to J.J.M.), the University of Michigan Rogel Cancer Center Support Grant (P30CA46592 to J.J.M.), and the Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(RS-2023-00243005 to Y.K.)