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

Abstract

Considering the limited intratumoral drug accumulation and the immunosuppressive tumor microenvironment that restrict the efficacy of conventional treatments, complete tumor eradication remains a formidable challenge. Herein, a near-infrared 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 a photothermal material, iron oxide (Fe₃O₄) nanoparticles as a ferroptosis inducer, and specific pyroptotic antigens, which are encapsulated in a nanostructure containing thermosensitive lipid shells. Due to the existence of Fe₃O₄ nanoparticles, the designed nanoinducer (SP@CSFe) shows remarkably increased accumulation at tumor sites via magnetic navigation. As such, SP@CSFe generates localized heat via 808 nm laser irradiation to realize photothermal therapy (PTT), which triggers a phase transition of thermosensitive lipid shells to release both Fe₃O₄ nanoparticles and pyroptotic antigens. Subsequently, the exposed Fe₃O₄ nanoparticles catalyze the 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 is significantly inhibited and survival rates are markedly improved. By 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 effects for effective and precise cancer therapy.