Tumor‐Selective Biodegradation‐Regulated Photothermal H₂S Donor for Redox Dyshomeostasis‐ and Glycolysis Disorder‐Enhanced Theranostics

Abstract H₂S‐mediated tumor therapy has received great attention due to its unique physiological activity and synergistical enhancement, but suffers from limited H₂S donors with promised biosafety to regulate the H₂S delivery and subsequently the elusive pathway to augment the combined therapy. Herein, a PEGylated porous molybdenum disulfide nanoflower (MSP) with abundant defects is facilely synthesized for tumor‐targeted theranostics. MSP possesses good water‐dispersity and high photothermal ability, which is used for photoacoustic imaging and photothermal therapy. Interestingly, MSP is selectively degraded upon exposure to superfluous glutathione (GSH) within tumor cells, the mechanism of which is investigated, as a reduction‐coordination reaction. This special degradation induces redox dyshomeostasis via GSH depletion for reactive oxygen species‐accumulated chemodynamic therapy. Meanwhile, the selective biodegradation of MSP regulates a sustained H₂S release within tumor and achieves a targeted H₂S gas therapy via enhancing the glycolysis to acidify the tumor cells (glycolysis disorder). Synergistically, these performances are further enhanced via near‐infrared photothermal heating, where excellent therapeutic outcomes with good biosafety are accomplished in vitro and in vivo. These characteristics, together with the unique biodegradation and no obvious side‐effects of the nanoparticles, suggest a potential therapeutic strategy for precise tumor treatments.