Magnetically navigated and near-infrared programmable nanoinducers for co-activating pyroptosis and ferroptosis in antitumor immunotherapy

Abstract

In consideration of the limited intratumoral drug accumulation and immunosuppressive tumor microenvironment that restrict the efficacy of conventional treatments, complete tumor eradication is still a formidable challenge. Herein, a nearinfrared programmable nanoinducer that can co-activate pyroptosis and ferroptosis is constructed for potent antitumor immunotherapy via exogenous magnetic navigation. The nanoinducer consists of a semiconducting polymer (SP) as photothermal materials, iron oxide (Fe3O4) nanoparticles as a ferroptosis inducer, and specific pyroptotic antigens, which are encapsulated into a nanostructure containing thermosensitive lipid shells. Due to the existence of Fe3O4 nanoparticles, the designed nanoinducers (SP@CSFe) show a remarkably increased accumulation in tumor sites via magnetic navigation.As such, SP@CSFe generate localized heat via 808 nm laser irradiation to realize photothermal therapy (PTT), which triggers a phase transition of the thermosensitive lipid shells to release both Fe3O4 nanoparticles and pyroptotic antigens.Subsequently, the exposed Fe3O4 nanoparticles catalyze Fenton reaction to induce intracellular ferroptosis, while the released pyroptotic antigens can recruit immune cells and sensitize the immune system. Through such a magnetic navigation and programmable controlled release mechanism, a potent antitumor immunological effect is triggered by the synergy of PTT, ferroptosis and pyroptosis immunotherapy. Therefore, tumor growth in subcutaneous breast cancer mouse models are significantly inhibited and survival rates are markedly improved. Via combining with programmed death-ligand 1 antibody (aPD-L1) immunotherapy, SP@CSFe can trigger an immunological memory to suppress tumor recurrence. This study offers a magnetically targeted and programmable nanoinducer to integrate PTT ablation with pyroptosis-ferroptosis-induced immunogenic effect for effective and precise cancer therapy.