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

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 (H₂O₂), 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 H₂O₂ to modulate the intracellular redox microenvironment. Incorporation of cEIL as a chaperone within LNP (ceLNP) enables adaptive vitamin E release upon encountering elevated H₂O₂ 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.