Thuy Giang Nguyen Cao a,1, Quan Truong Hoang a,1, Ji Hee Kang b,1, Su Jin Kang a,1, Vasanthan Ravichandran a, Won Jong Rhee a,c, Minjong Lee d,e, Young Tag Ko b, Min Suk Shim a
aDivision of Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
bCollege of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea
cResearch Center for Bio Materials & Process Development, Incheon National University, 119 Academy-ro, Yeonsu-gu, Incheon, 22012, Republic of Korea
dDepartment of Internal Medicine, Ewha Womans University College of Medicine, Seoul, 07804, Republic of Korea
eDepartment of Internal Medicine, Ewha Womans University Medical Center, Seoul, 07804, Republic of Korea
1These authors contributed equally to this work.
Corresponding authors: Won Jong Rhee, Minjong Lee, Young Tag Ko, Min Suk Shim
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.