A Biomimetic Photothermal Nanoplatform for Epigenetic-Driven Tumor Immunotherapy and Immune Memory Induction

Breast cancer remains a major clinical challenge due to its high recurrence and metastatic potential. Here, we develop a multifunctional photothermal nanocomposite, GS@AM@M, integrating gold nanorods and mesoporous silica for synergistic photothermal-epigenetic immunotherapy. GS@AM@M exhibits excellent photothermal conversion efficiency under NIR-II (808 nm) irradiation, while its mesoporous framework enables efficient coloading of the DNA methyltransferase inhibitor 5-azacytidine (5-Aza) and the histone deacetylase inhibitor mocetinostat (MGCD). To enhance tumor targeting and immune evasion, the nanocomposite is camouflaged with macrophage-derived cell membranes. Upon NIR-II irradiation, GS@AM@M accumulates within tumors and enables controlled drug release. The combined therapy induces immunogenic cell death (ICD), promotes dendritic cell maturation, and activates cytotoxic CD8⁺ T cells. Meanwhile, epigenetic reprogramming of the MYC/Type I IFN signaling axis enhances CCL5 secretion, thereby recruiting and amplifying CD8⁺ T-cell responses. This synergistic mechanism effectively eradicates both primary and metastatic tumors while establishing durable immune memory to prevent recurrence. By integrating photothermal therapy, immunotherapy, and epigenetic modulation, GS@AM@M provides a potent and precise platform for comprehensive breast cancer treatment.