Electro-activated nanozyme for in situ tumor vaccination: Synergistic multi-enzyme catalysis and electrodynamic therapy

Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with poor prognosis and limited treatment options. To address the challenges of conventional therapy resistance, antioxidant defence, and immune evasion, we developed a multifunctional nanozyme platform, MIL-100(Fe)@Pt@R837@HA (HMPR), that integrates electrodynamic therapy (EDT), chemodynamic therapy, and immunotherapy. The multi-enzyme activities of HMPR allow for the oxygen generation, hydroxyl radicals production, and glutathione depletion, thereby alleviating hypoxia and triggering both apoptosis and ferroptosis. Under electrical stimulation, HMPR promotes significant production of reactive oxygen species via Pt-mediated EDT to amplify ferroptosis and immunogenic cell death (ICD). In addition, the tumor-specific GSH level triggers the release of the immune adjuvant R837. The potent ICD effect, combined with the sustained release of the adjuvant R837, endows the nanozyme HMPR with the characteristics of an in situ "tumor vaccine", continuously promoting dendritic cell maturation, activating T cell-mediated immunity, and establishing long-term immunological memory to prevent tumor recurrence and inhibition of distant tumor growth. This cascade effect reprograms the immunosuppressive tumor microenvironment into an immunostimulatory one, significantly enhancing the efficacy of PD-1 blockade. Our study provides a powerful electro-enhanced nanozyme-immune synergistic strategy for OSCC and offers a flexible platform adaptable to other solid tumors.