Hypoxia-responsive COF nanomedicine co-delivers gambogic acid and BODIPY for synergistic lung cancer PDT suppression

• Hypoxia-responsive COF carrier co-delivers GA & BODIPY, reducing toxicity. • Synergistic chemo-PDT inhibits lung cancer growth in vitro/vivo. • Enables real-time monitoring via fluorescence quenching; high biosafety. The hypoxic tumor microenvironment (TME) in lung cancer contributes significantly to therapeutic resistance. To address this, we developed a hypoxia-responsive nanomedicine, BG@COF-AZO, using an azobenzene-functionalized covalent organic framework (COF) for the co-delivery of gambogic acid (GA) and a BODIPY photosensitizer. This carrier enables selective drug release under hypoxic conditions, minimizing off-target toxicity. Comprehensive characterization confirmed successful synthesis, high stability, and efficient drug loading. In vitro, the system demonstrated excellent biocompatibility and hypoxia-enhanced efficacy, inhibiting proliferation and inducing apoptosis in A549 and H1299 lung cancer cells. The combination of GA chemotherapy and BODIPY-mediated photodynamic therapy (PDT), activated by a 488 nm laser, produced strong synergistic antitumor effects. In vivo studies in an A549 subcutaneous tumor model showed that BG@COF-AZO plus PDT significantly suppressed tumor growth, with high tumor accumulation and no evident systemic toxicity, as confirmed by serum biochemistry and histopathology. This work highlights the potential of hypoxia-responsive COFs for targeted lung cancer therapy and integrates natural compounds like GA into synergistic treatment regimens.