Hypoxia-Activated Biodegradable Porphyrin-Based Covalent Organic Frameworks for Cancer Ferroptosis Therapy through Multiple Regulatory Pathways

Ferroptosis therapy efficacy in cancer is seriously restricted by the overexpression of glutathione (GSH) and hypoxia. Herein, a hypoxia-activated biodegradable porphyrin-based covalent organic framework (HPCOF) loading l-buthionine sulfoximine (BSO) and Fe³⁺, followed by modification with hyaluronic acid (HA), is fabricated (BFCOF) for antitumor therapy through multiple regulatory pathways. BFCOF could produce singlet oxygen (¹O₂) and hydroxyl radicals (·OH), which not only induce apoptosis and necrosis but also promote lipid peroxidation (LPO) accumulation, resulting in ferroptosis. The loaded BSO could block the biosynthesis of GSH, combined with the self-cycling valence alternations of Fe³⁺/Fe²⁺, and the intracellular GSH is consumed and decreased, which results in the inactivation of glutathione peroxidase 4 (GPX4) and the accumulation of LPO, eventually inducing synergistically enhanced ferroptosis. The ferroptosis dominated by the above reactions synergizes with BFCOF-mediated photothermal therapy to improve the efficacy of cancer therapy. Moreover, the reaction between Fe³⁺ and H₂O₂ also produces O₂, alleviating tumor hypoxia. Importantly, BFCOF has a response to the tumor microenvironment and could be degraded for clearance, exhibiting excellent biosafety. The obtained BFCOF presents a new strategy for effectively improving ferroptosis efficiency and multimodal cancer therapies.