Provoking endogenous protein-derived Zn2+ de-hijacking for metalloimmunotherapy

Metalloimmunotherapy involves utilizing metal ions to achieve promising immunotherapy. However, the exogenous metal ions may cause unexpected severe side effects in metalloimmunotherapy due to the unstable and non-specific characteristics of nanomaterials. Herein, drawing inspiration from the utilization of endogenous intracellular Zn-storing proteins, a nonmetallic nanodrug has been developed to induce the endogenous protein-derived Zn²⁺ de-hijacking for metalloimmunotherapy. Specifically, the nonmetallic nanodrug was designed using disulfide-doped hollow organosilicon co-loaded with 5-aminolevulinic acid and glutathione-responsive nitric oxide (NO) donor (NIC), functioning as a STING activator. Upon internalization, subsequent near-infrared laser irradiation can prompt the STING activator to elicit mitochondrial impairment and discharge mitochondrial DNA, thereby initiating the STING pathway. Simultaneously, the interplay between NIC and glutathione results in the production of NO to induce the liberation of protein-derived Zn²⁺, thereby promoting STING activation without necessitating additional metal uptake. Overall, this work provides a safe and promising strategy for the development of metalloimmunotherapy.