Multifunctional Oxygen-Generating Nanoflowers for Enhanced Tumor Therapy

Sonodynamic therapy (SDT) and chemotherapy have received great attention as effective methods for tumor treatment. However, the inherent hypoxia of the tumor greatly hinders its therapeutic efficacy. In this work, a tumor microenvironment-responsive biodegradable nanoplatform SiO2-MnO2-PEG-Ce6&DOX (designated as SMPC&D) is fabricated by encapsulating manganese oxide (MnO2) into silica nanoparticles and anchoring poly(ethylene glycol) (PEG) onto the surface for tumor hypoxia relief and delivery, then loaded with sonosensitizer Chlorin e6 (Ce6) and chemotherapeutic drug doxorubicin (DOX) for hypoxic tumor treatment. We evaluated the physicochemical properties of SMPC&D nanoparticles and the tumor therapeutic effects of chemotherapy and SDT under ultrasound stimulation in vitro and in vivo. After endocytosis by tumor cells, highly expressed glutathione (GSH) triggers biodegradation of the nanoplatform and MnO2 catalyzes hydrogen peroxide (H2O2) to generate oxygen (O-2), thereby alleviating tumor hypoxia. Depleting GSH and self-supplying O-2 effectively improve the SDT efficiency both in vitro and in vivo. Ultrasonic stimulation promoted the release and cellular uptake of chemotherapy drugs. In addition, the relieved hypoxia reduced the efflux of chemotherapy drugs by downregulating the expression of the P-gp protein, which jointly improved the effect of chemotherapy. This study demonstrates that the degradable SMPC&D as a therapeutic agent can achieve efficient chemotherapy and SDT synergistic therapy for hypoxic tumors.

Automated summary

Sonodynamic therapy (SDT) and chemotherapy have been combined using a tumor microenvironment-responsive biodegradable nanoplatform to treat hypoxic tumors, resulting in improved therapeutic efficacy. The nanoplatform encapsulates manganese oxide (MnO2) into silica nanoparticles and incorporates a sonosensitizer (Ce6) and a chemotherapeutic drug (DOX), which are released in response to glutathione (GSH) and catalyzed by MnO2 to generate oxygen (O-2), alleviating tumor hypoxia. Ultrasonic stimulation further enhances chemotherapy drug release and cellular uptake, while also downregulating P-gp protein expression to reduce drug efflux. This study demonstrates the potential of the nanoplatform for efficient chemotherapy and SDT synergistic therapy for hypoxic tumors.