A covalent tumor-targeted theranostic system for NIR imaging-guided photodynamic-ferroptosis synergistic therapy of lung cancer
Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality, with conventional therapies hampered by poor tumor specificity, low drug accumulation, and suboptimal efficacy. To address these challenges, we rationally designed a tumor-targeted, ferrocene-bearing, covalently immobilizable theranostic probe, dIR-CDF, for near-infrared (NIR) imaging-guided photodynamic-ferroptosis synergistic therapy. The probe exploits the overexpression of sulfenated proteins in the tumor microenvironment to specifically target integrin αvβ3-positive NSCLC cells and undergo covalent anchoring via the reaction between 1,3-cyclohexanedione and sulfenic acid, thereby enhancing tumor accumulation and retention. Under 808 nm irradiation, dIR-CDF generates singlet oxygen (1O2) for photodynamic therapy (PDT), while the sustained release of ferrocene catalyzes Fenton reactions to produce hydroxyl radicals (·OH), inducing ferroptosis. The synergistic action of PDT and ferroptosis amplifies lipid peroxidation and disrupts antioxidant defenses, leading to efficient suppression of NSCLC tumors in living mice. This work presents a universal and powerful theranostic platform for precise cancer diagnosis and treatment, with the covalent targeting strategy offering enhanced specificity and retention.