Bioreducible exosomes encapsulating glycolysis inhibitors potentiate mitochondria-targeted sonodynamic cancer therapy via cancer-targeted drug release and cellular energy depletion

Nanocarrier-assisted sonodynamic therapy (SDT) has shown great potential for the effective and targeted treatment of deep-seated tumors by overcoming the critical limitations of sonosensitizers. However, in vivo SDT using nanocarriers is still constrained by their intrinsic toxicity and nonspecific cargo release. In this study, we developed bioreducible exosomes for the safe and tumor-specific delivery of mitochondria-targeting sonosensitizers [triphenylphosphonium-conjugated chlorin e6 (T-Ce6)] and glycolysis inhibitors (FX11). Redox-cleavable diselenide linker-bearing lipids were embedded into exosomes to trigger drug release in response to overexpressed glutathione in the tumor microenvironment. Bioreducible exosomes facilitate the cytoplasmic release of their payload in the reducing environment of tumor cells. They significantly enhance drug release and sonodynamic effects when irradiated with ultrasound (US). The mitochondria-targeted accumulation of T-Ce6 efficiently damaged the mitochondria of the cells under US irradiation, accelerating apoptotic cell death. FX11 substantially inhibited cellular energy metabolism, potentiating the antitumor efficacy of mitochondria-targeted SDT. Bioreducible exosomes effectively suppressed tumor growth in mice without significant systemic toxicity, via a combination of mitochondria-targeted SDT and energy metabolism-targeted therapy. This study offers new insights into the use of dual stimuli-responsive exosomes encapsulating sonosensitizers for safe and targeted sonodynamic cancer therapy. Bioreducible DSe-E(T-Ce6/FX11) facilitates the cytoplasmic release of T-Ce6 and FX11 in the GSH-rich microenvironment of tumor cells. Ultrasound exposure activates T-Ce6 to produce ROS in mitochondria, and FX11 inhibits the production of ATP in the cells, subsequently triggering the apoptosis through a combination of mitochondria-targeted sonodynamic tumor therapy and cellular energy depletion. [Display omitted]