Hypoxia-Activatable Nanovesicles as In Situ Bombers for Combined Hydrogen-Sulfide-Mediated Respiration Inhibition and Photothermal Therapy.

Photothermal therapy (PTT) has emerged as a promising alternative or supplement to cancer treatments. While PTT induces the ablation of solid tumors, its efficiency is hampered by self-recovery within impaired cancer cells through glycolysis and respiration metabolism. Based on this, the introduction of hydrogen sulfide (H 2 S)-mediated respiration inhibition is a good choice to make up for the PTT limitation. Herein, nanovesicles ( NP1 ) are integrated by a hypoxia-responsive conjugated polymer ( P1 ), polymetric H 2 S donor ( P2 ), and near-infrared (NIR) light-harvesting aza-BODIPY dye ( B1 ) for the delivery of H 2 S and synergistic H 2 S gas therapy/PTT. The scaffold of NP1 undergoes disassembly in the hypoxic environments, thus triggering the hydrolysis of P2 to continuously long-term release H 2 S. Dependent on the superior photothermal ability of B1 , NP1 elicits high photothermal conversion efficiency (η = 19.9%) under NIR light irradiation for PTT. Moreover, NP1 serves as in situ H 2 S bombers in the hypoxic tumor environment and suppresses the mitochondrial respiration through inhibiting expression of cytochrome c oxidase (COX IV) and cutting off the adenosine triphosphate (ATP) generation. Both in vitro and in vivo results demonstrate good antitumor efficacy of H 2 S gas therapy/PTT, which will be recommended as an advanced strategy for cancer therapeutics.