Enhanced cancer therapy by hypoxia-responsive copper metal-organic frameworks nanosystem

Tumor hypoxia-responsive size-switchable nanosystems for precise delivery of drug into deep tumor show great prospects for killing cancer cells with high specificity and minimal invasiveness. However, the development of versatile nanosystems is still a challenge. Herein, for the first time, we report a novel hypoxia-responsive copper metal-organic framework nanoparticles (Cu-MOF NPs) for chemodynamic therapy and sonodynamic therapy (CDT/SDT). The large size Cu-MOF NPs show good stability under normal oxygen partial pressure and enhance tumor accumulation, and it quickly degraded and released Cu²⁺ and Ce6 when exposed to the hypoxic tumor microenvironment (TME), significantly reinforced the intratumoral penetration. The internalized Cu²⁺ reacts with local GSH to deplete GSH and reduce Cu²⁺ to Cu⁺, which subsequently reacts with endogenous H₂O₂ to produce cytotoxic hydroxyl radicals (•OH) through Fenton-like reaction for CDT. The released Ce6 further mediated SDT under US irradiation. The synergistic SDT/CDT efficacy was significantly enhanced owing to the GSH depletion, realizing selective and effective MCF-7 killing with minimal invasiveness. This work presents a novel hypoxia-responsive MOF nanosystem with intrinsic CDT properties, mainly, the MOF nanosystem is flexible to the integration with other therapy approaches. It provides a general strategy to design a hypoxia-responsive MOF nano theranostic platform.