An All-in-One Attack: Microneedle-Delivered Bio-Hybrid Nanoagonist for Tumor Immunotherapy.

Standard treatments for oral squamous cell carcinoma (OSCC), including surgery, radiotherapy, and chemotherapy, are often ineffective in preventing recurrence. This challenge is largely attributed to the persistently high recurrence rates driven by the highly immunosuppressive tumor microenvironment (TME). Here, we develop a dissolvable gelatin methacryloyl (GelMA-PVA) microneedle patch for localized delivery of a bio-hybrid nanocomplex, MPN@Pg-OMVMel, designed to synergistically eradicate tumors and remodel the TME. The nanocomplex, formed by coating Melanin-containing bacterial outer membrane vesicles from Porphyromonas gingivalis (Pg-OMVMel)with an iron-tannic acid metal-phenolic network (MPN), mediates potent photothermal therapy under 808 nm laser irradiation. Simultaneously, the MPN coating consumes intratumoral H2O2 to generate hydroxyl radicals via the Fenton reaction, triggering ferroptosis. In murine OSCC models, this combination induces immunogenic cell death and successfully reprograms tumor-associated macrophages from a pro-tumor M2 to an anti-tumor M1 phenotype. The treatment additionally induced robust immunogenic cell death, as evidenced by calreticulin exposure and HMGB1 release, leading to enhanced dendritic cell maturation. Consequently, the treatment achieved superior tumor suppression and significantly reduced recurrence compared to controls, establishing a robust and sustained antitumor immune response. This localized platform presents a promising strategy for managing OSCC by effectively overcoming the limitations of current therapies.