Lipid Nanoparticle Chaperone with Redox-Adaptive Intracellular Microenvironment Modulation Potentiates the Potency of mRNA Vaccines.

Antigen presentation is a critical driver of cytotoxic antitumor immunity and a limiting factor in mRNA vaccine efficacy. The overabundance of intracellular reactive oxygen species, such as hydrogen peroxide (HO), generated during LNP@mRNA transfection severely compromises the mRNA translation efficiency, and the resultant lipid peroxidation further disrupts antigen-presenting pathways. Herein, we screen 96 antioxidants and identify vitamin E as a potentiator of LNP to drastically promote the translation efficiency of mRNA and antigen presentation by dendritic cells. We design and synthesize a vitamin E-modified ionizable lipid (cEIL) linked by an oxalate ester, which is susceptible to cleavage by HO to modulate the intracellular redox microenvironment. Incorporation of cEIL as a chaperone within LNP (ceLNP) enables adaptive vitamin E release upon encountering elevated HO during transfection, which expedites the restoration of intracellular redox homeostasis, thus reinforcing the translation efficiency and mitigating lipoperoxidation to bolster the antigen presentation through the HSP70-mediated MHC I pathway. mRNA vaccines fabricated from ceLNP elicit strong antitumor immune responses to suppress tumor growth and inhibit tumor metastasis across multiple models, including melanoma, colon cancer, and neoantigen-expressing tumors, both as standalone treatments and in combination with immunotherapy or chemotherapy. This vitamin E-chaperoned delivery system holds immense promise as a universal platform for the development of next-generation mRNA vaccines in cancer immunotherapy with potent efficacy and safety.