Activatable and Self-Monitoring Hydrogen Sulfide-Based Molecular Senomorphics for Visualized Regulation of Cellular Senescence

Specific regulation of the senescence-associated secretory phenotype (SASP) is vital to block senescence-induced detrimental cellular plasticity. Recently, some chemical compounds called senomorphics have demonstrated such potential, but it remains challenging to achieve site-specific activation and real-time monitoring of the action of seno-morphics, posing great obstacles for transformable applications. Here, we report a tailor-made hydro-gen sulfide (H2S) donor (Lyso-FH2S-Gal) as a new class of molecule senomorphics for spatially con -trolled delivery of H2S for visualization of regulation of cellular senescence. It comprises four functional moieties in a single molecular structure, including a lysosome-targeting group for cell recognition, a lysosomal enzyme-cleaved scaffold for site-specific activation, thiocarbamate as the H2S precursor, and a switchable fluorophore for concurrent self-reporting of H2S release and senescence imaging. Lyso-FH2S-Gal exhibited remarkable response selectivity, sustained H2S release, and 141-fold fluorescence enhancement. In cellular models, Lyso-FH2 S-Gal preferentially enriched in senescent cells over nonsenescent cells, and alleviated the levels of SASP and reactive oxygen species (ROS) in senescent cells, while remaining inert in nonsenescent cells. More impressively, it efficiently inhibited the SASP-mediated crosstalk between senescent cells and surrounding nonsenescent cells, thereby preventing senescence propagation. This work offers a useful molecular tool with the hope for controlled intervention of senescence-related important biological processes.