Self-amplifying hypoxia cascade in covalent organic framework/metal organic framework nanoreactors for synergistic cancer therapy

Tumor hypoxia, a hallmark of the tumor microenvironment (TME), drives malignancy and therapeutic resistance but also offers a target for selective therapy. Hypoxia-activated prodrugs (HAPs) like TH-302 exploit this niche, yet their efficacy is often limited by insufficient hypoxia levels. To overcome this limitation, a hypoxia-responsive nanoplatform COF@MOF/TH-302@HA was designed to intensify tumor hypoxia and trigger a self-amplifying therapeutic cascade. The platform was constructed by growing a hypoxia-sensitive copper-based metal-organic framework (Cu-MOFs) on a nitrogen-rich porphyrinic covalent organic framework (p-COFs) core, followed by loading of the HAP TH-302 and coating with hyaluronic acid for tumor targeting. Upon accumulation in the tumor, the degradation of the Cu-MOFs shell in the hypoxic microenvironment released Cu²⁺ ions and TH-302. The p-COFs core enabled near-infrared laser-triggered photothermal and photodynamic therapy (PDT). Crucially, the oxygen consumption during PDT further aggravated hypoxia, which in turn accelerated the degradation of the Cu-MOFs, establishing a feedback loop that amplified the release and efficacy of both TH-302 and Cu²⁺. Simultaneously, photothermal therapy (PTT) enhanced the Cu²⁺-mediated Fenton-like reaction. This coordinated action of chemodynamic therapy, photothermal therapy, PDT, and hypoxia-activated chemotherapy resulted in effective tumor suppression both in vitro and in vivo with minimal systemic toxicity. This work presents a novel strategy for leveraging the TME to achieve self-enhanced synergistic therapy.