Apoptotic mimicry lipid nanoparticles with dendritic cell tropism effectively boost mRNA cancer vaccine efficacy and induce long-lived memory T cells by mitigating inflammation 2775

Description The COVID-19 pandemic accelerated the development of mRNA vaccines, such as Spikevax and Comirnaty, delivered via lipid nanoparticles (LNPs). Despite this success, conventional mRNA LNPs lack cell specificity, particularly for dendritic cells (DCs), which are crucial for antitumor immunity. Moreover, the inflammatory nature of LNPs raises safety concerns, with debate over their impact on the tumor therapeutic effectiveness by inducing effector or memory T cells. Phosphatidylserine (PS) on apoptotic cells acts as an ‘eat-me’ signal, prompting phagocytes like DCs to clear them through efferocytosis, thereby preventing inflammation. Inspired by this PS biology, we have developed a new PS-containing LNP (PS-LNP) that can target mRNA to DCs and improve antigen expression with minimal inflammation. Apoptotic mimicry PS-LNP enhanced antigen presentation by DCs and CD8+ T cell priming in vitro, delivered mRNA more effectively to DCs in mouse lymph nodes, and significantly reduced inflammation-related pathways, including type-I interferon, compared with Spikevax LNP. In antitumor efficacy studies, immunization with mRNA vaccines delivered via PS-LNP significantly inhibited tumor growth and markedly increased antigen-specific CD8+ memory precursor effector and memory T cells without triggering inflammation, compared with Spikevax LNP. Our study showed that apoptotic mimicry LNP can improve mRNA cancer vaccines by targeting DCs and alleviating inflammation. Funding Sources This work was supported by NIH (R01AI127070, R01CA210273, U01CA210152, R01DK108901, R01DE026728, R01DE030691, R01DE031951), the University of Michigan Rogel Cancer Center Support Grant (P30CA46592), and Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(RS-2023-00243005).