"Dual-lock" activated nanosystem for colorectal cancer: Defect engineering-driven NIR-II PTT-enhanced ferroptosis to trigger antitumor immunity.

Abstract

Conventional therapies for colorectal cancer (CRC) are often constrained by limited specificity, while the hypoxic, acidic, and immunosuppressive commonly contributes to immunotherapy resistance. Herein, a dual-responsive nanosystem with oxygen vacancies (AgFeO₂-PVP, termed Vo-AFP) was engineered against CRC. This system is selectively activated within the tumor microenvironment (TME) by H₂S and acidic conditions, triggering Fe²⁺ release to induce ferroptosis and forming a dual-vacancy structure composed of iron and oxygen vacancies. These defects introduce sub-bandgap (intermediate energy bands) that facilitate two-step single-photon absorption under 1064 nm laser irradiation and promote non-radiative electron-hole recombination, boosting photothermal conversion efficiency from 17.03% to 34. 15%. Density functional theory (DFT) calculations confirm that the dual-vacancy configuration induces charge redistribution, enhancing localized surface plasmon resonance (LSPR) in the Near-infrared II (NIR-II) window. The synergy between defect-assisted sub-bandgap absorption and LSPR enhancement enables effective photothermal ablation of deep tumors. In vivo results show that localized heating further accelerates Fe²⁺ release and suppresses the GPX4-mediated antioxidant pathway, augmenting ferroptotic death. This photothermal-enhanced ferroptosis significantly sensitizes tumors to aPD-L1 checkpoint blockade, remodels the immunosuppressive microenvironment, activates systemic antitumor immunity, and inhibits tumors and pulmonary lesions. Vo-AFP thus provides an integrated theranostic platform and a new paradigm for activatable, defect-engineered nanosystem in CRC immunotherapy.