Acid‐Responsive Nanoregulators Elicit Hydrogen Sulfide‐Mediated Tumor Oxygenation and Selective Sonosensitization for Hypoxic Tumors

Abstract Oxygen (O ₂ ) tension within a tumor is considered a hallmark of sonodynamic therapy (SDT). Herein, multifunctional nanoregulators, CMCS‐Au‐SrS (CAS), are reported, which are assembled by carboxymethyl chitosan(CMCS) tethered gold nanoclusters (Au NCs) as sonosensitizers and sulfurate donors strontium sulfide nanoparticles (SrS NPs), to evoke selective SDT in hypoxic tumors. CAS possess tumor‐acidity responsiveness to form large‐size aggregated Au NCs with shortened bandgap so that effectively induce powerful reactive oxygen species generation. On the other hand, acidity triggers the degradation of SrS NPs and release hydrogen sulfide (H ₂ S), evoking tumor oxygenation to overcome hypoxia. This in junction with the accelerated sonosensiting ability boosts amplified SDT efficacy. More importantly, specific glycolysis induced acidification leads to CAS selectively accumulated in cancer cells, further guaranteeing the execution of the advanced therapeutic manners. Additionally, doping Nd ³⁺ in SrS NPs endows CAS with the second near‐infrared fluorescence to facilitate the in vivo tracing property with good tissue penetration (up to 6 mm). This strategy may play a pioneering role to develop theranostic reagents with improved tumor enrichment capacity and enhanced SDT in hypoxia tumors.