Retinoic Acid–Functionalized Lipid Nanoparticles Reprogram Splenic Immunity for Potent mRNA Cancer Vaccination

ABSTRACT Lipid nanoparticle (LNP)–enabled messenger RNA (mRNA) vaccines hold great promise for cancer immunotherapy, yet their clinical translation is often limited by insufficient delivery to secondary lymphoid organs and limited immune activation. Here, we design a redox‐responsive, all‐trans‐retinoic acid (ATRA)–functionalized PEG lipid (ATRA‐SS‐PEG, ASP) as a functional alternative to conventional DMG‐PEG for LNP formulation. ASP incorporation preserves LNP colloidal stability while promoting spleen‐oriented mRNA expression and efficient cytosolic release through intracellular redox‐triggered PEG shedding. Mechanistic comparison with a non‐cleavable ATRA‐PEG analogue confirms the functional contribution of the disulfide linkage to lysosomal escape and mRNA expression. ASP‐LNPs enhance splenic antigen expression, presentation, and immune activation, thereby reprogramming the splenic immune microenvironment toward effective immune priming. Notably, ASP‐LNPs maintain robust mRNA expression upon repeated administration, suggesting improved repeat‐dosing performance. As a proof of concept, ASP‐LNPs encoding ovalbumin (OVA) elicit potent antitumor immunity in B16‐OVA melanoma and pulmonary metastasis models, promoting effector T‐cell infiltration and suppressing tumor progression with a favorable safety profile. Collectively, this work establishes a spleen‐targeted and immunomodulatory LNP platform that integrates stimulus‐responsive cytosolic release with the intrinsic adjuvant activity of ATRA‐conjugated lipids, providing a versatile paradigm for next‐generation mRNA cancer vaccines.