A Biomimetic Nanovesicle‐Based Synthetic Vaccine Platform Through Co‐Anchoring Oxidized Phospholipid and CpG for Rejuvenating Antitumor Immunity in Aged Mice

ABSTRACT Despite advances in immunotherapy, the efficacy against melanoma remains limited in aged individuals, primarily due to diminished dendritic cell (DC) function and an immunosuppressive tumor microenvironment. To address this, we report a chemically engineered “tumor ghost” nanovaccine (dMVac) constructed through a biomimetic synthesis strategy. The core nanovesicles are derived from separate melanoma cells subjected to hypochlorous acid oxidation and UVB radiation, respectively, enriching them with a broad spectrum of tumor antigens and endogenous damage‐associated molecular patterns. These nanovesicles are further functionalized via lipid‐insertion chemistry to co‐anchor the DC‐hyperactivating molecules: the oxidized phospholipid PGPC and cholesterol‐conjugated CpG oligonucleotide. This surface engineering enables efficient lymph node targeting and promotes synergistic DC activation. The resulting dMVac reverses age‐related DC dysfunction by enhancing their activation, migration, and IL‐1β secretion, thereby stimulating robust cytotoxic T‐cell responses and memory formation in aged mice. Moreover, dMVac synergizes with doxorubicin (DOX) and anti‐PD‐1 therapy to reprogram the immunosuppressive tumor microenvironment via enhanced antigen presentation and T‐cell infiltration, leading to significant suppression of tumor progression. This work demonstrates how rational chemical design of a bio‑hybrid nanovaccine can overcome age‐associated immune dysfunction, providing a versatile platform for cancer immunotherapy.