Engineered Ginseng‐Derived Nanovesicles with MCSP Targeting and Mitochondria‐Directed Prodrug Delivery for Synergistic Immunotherapy of Metastatic Melanoma

Abstract Metastatic melanoma (MM) remains highly lethal and poorly responsive to current immunotherapies owing to its heterogeneity, immunosuppressive tumor microenvironment (TIME), and metastatic potential. Precision therapeutics that simultaneously target tumors, reverse TIME suppression, and block metastasis are urgently needed. Triptolide (TP), a small‐molecule compound, has emerged as a promising antitumor agent: it induces apoptosis via the mitochondria‐mediated intrinsic pathway and triggers immunogenic cell death (ICD) to activate antitumor immunity. However, its severe systemic toxicity and extremely short half‐life hinder clinical translation. To address this, a multifunctional targeted nanoplatform (G‐NVs‐MCSP/pTP) is engineered by encapsulating a mitochondria‐directed triptolide prodrug (triptolide palmitate, pTP) into ginseng‐derived nanovesicles (G‐NVs) and functionalizing the surface with a melanoma‐specific MCSP‐scFv. MCSP‐scFv recognizes MCSP‐overexpressing melanoma cells and inhibits FAK/MAPK signaling to suppress metastasis. After fusion, pTP is internalized via enhanced fatty acid uptake, metabolized in mitochondria to release TP, thereby inducing mitochondrial dysfunction and apoptosis. G‐NVs and TP synergistically remodel TIME: G‐NVs induce TLR4‐dependent M1 polarization, while TP triggers ICD via CRT/HMGB1 release, promoting DC maturation and T‐cell infiltration. G‐NVs‐MCSP/pTP show strong antitumor efficacy and biosafety in xenograft, humanized, and PDX models. This platform integrates immune activation, apoptosis induction, and metastasis suppression, offering a translational strategy to overcome MM resistance.