Exosome membrane-sheathed and multi-stimuli-responsive MnO2 nanoparticles with self-oxygenation and energy depletion abilities potentiate the sonodynamic therapy of hypoxic tumors

Sonodynamic therapy (SDT), which employs ultrasound (US) to activate sonosensitizers to generate reactive oxygen species (ROS), has emerged as an effective approach for treating deep-seated tumors. However, poor biocompatibility of sonosensitizers and hypoxic tumor microenvironments are significant challenges for in vivo SDT. Herein, hollow manganese dioxide nanoparticles (MnO2 NPs) encapsulating the sonosensitizer, indocyanine green (ICG), were developed for enhanced sonodynamic cancer therapy by high ICG loading and tumor hypoxia relief. A glycolysis inhibitor, FX11, was co-loaded into MnO2 NPs to boost SDT efficacy via FX11-induced energy depletion. Because of the high biocompatibility, low immunogenicity, and efficient intracellular delivery of exosomes, ICG- and FX11-loaded MnO2 NP [M(ICG/FX11)] was coated with exosome membranes for safe and efficient in vivo SDT. The exosome membrane-coated M(ICG/FX11) [Exo-M(ICG/FX11)] exhibited triple pH/H2O2/US-responsive drug release while avoiding premature drug leakage. Exo-M(ICG/FX11) was efficiently internalized by MCF-7 human breast cancer cells and catalyzed the endogenous H2O2 to generate O2 to relieve tumor hypoxia. Consequently, Exo-M(ICG/FX11) markedly boosted intracellular ROS levels upon US irradiation. Moreover, Exo-M(ICG/FX11) effectively inhibited glycolytic pathways, thereby potentiating the anticancer efficacy of SDT. An in vivo study using tumor-xenografted mice demonstrated that Exo-M(ICG/FX11) effectively accumulated in tumors and alleviated tumor hypoxia. Notably, Exo-M(ICG/FX11) combined with US substantially suppressed tumors in mice without causing systemic toxicity, owing to the synergistic effect of O2 supplied-SDT and energy-depleting chemotherapy. This study demonstrates that biomimetic Exo-M(ICG/FX11) is a safe and efficient nanoplatform for the treatment of hypoxic tumors.