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

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.