Inhalable nanoparticles with enhanced cuproptosis and cGAS–STING activation for synergistic lung metastasis immunotherapy

Due to the insufficient Cu+ accumulation, Cu+ efflux mechanism, and highly immunosuppressive tumor microenvironment (TME) in lung metastasis, the cuproptosis efficacy is limited. Herein, an inhalable nanodevice (CLDCu) is constructed to successfully overcome the drawbacks of cuproptosis. CLDCu consists of a Cu2+-chitosan shell and low molecular weight heparin-tocopherol succinate (LMWH-TOS, LT) core with disulfiram (DSF) loading. The prepared CLDCu can be inhaled and accumulate in large amounts in lung lesions (63.6%) with 56.5 times higher than intravenous injection. Within tumor cells, the mild acidity triggers the co-release of DSF and Cu2+, thus generating bis(diethyldithiocarbamate)-copper (CuET) to block Cu+ efflux protein ATP7B and forming toxic Cu+, leading to enhanced cuproptosis. Meanwhile, the released chitosan cooperates with CLDCu-induced cuproptosis to activate stimulator of interferon genes (STING) pathway, which significantly potentiates dendritic cells (DCs) maturation, as wells as evokes innate and adaptive immunity. In lung metastatic mice model, CLDCu is found to induce cuproptosis and reverse the immunosuppressive TME by inhalation administration. Moreover, CLDCu combined with anti-programmed cell death protein ligand-1 antibody (aPD-L1) provokes stronger antitumor immunity. Therefore, nanomedicine that combines cuproptosis with STING activation is a novel strategy for tumor immunotherapy.