Biodegradable BiOCl platform for oxidative stress injury-enhanced chemodynamic/radiation therapy of hypoxic tumors

Various physiological characteristics of the tumor microenvironment (TME), such as hypoxia, overexpression of glutathione (GSH) and hydrogen peroxide (H₂O₂), and mild acidity, can severely reduce the efficacy of many cancer therapies. Altering the redox balance of the TME and increasing oxidative stress can accordingly enhance the efficacy of tumor therapy. Herein, we developed a bismuth-based Cu²⁺-doped BiOCl nanotherapeutic platform, BCHN, able to self-supply H₂O₂ for TME-regulated chemodynamic therapy (CDT) combined with sensitized radiotherapy (RT). BCHN released H₂O₂ and consumed GSH to degrade the composite in the slightly acidic TME, and generated hydroxyl radicals (•OH) via a Fenton-like reaction catalyzed by copper ions, to achieve oxidative stress-enhanced CDT. The Fenton-like reaction also catalyzed H₂O₂ to produce O₂ to relieve tumor hypoxia, and combined with the X-ray-blocking property of bismuth to realize TME-enhanced radiotherapy. Synergistic CDT/RT has previously been shown to effectively inhibit tumor cell proliferation and achieve effective tumor control. The current results demonstrated a highly efficient multifunctional bio-degradable nanoplatform for oncotherapy. STATEMENT OF SIGNIFICANCE: Tumor microenvironment-modulated synergy of radiotherapy and chemodynamic therapy is conducive to rapid tumor ablation. Based on this principle, we fabricated a biodegradable BiOCl-based nanocomposite, BCHN. By supplying H₂O₂, a Fenton-like reaction generated •OH and O₂ catalyzed by copper ions, and consumed glutathione to biodegrade the composite. Overall, these actions increased tumor oxidative stress and realized the synergistic anti-tumor actions of chemodynamic therapy combined with bismuth-based sensitization radiotherapy. This strategy thus provides a unique approach to oncology therapy.