Aminopeptidase N‐Activated Self‐immolative Hydrogen Sulfide Donor for Inflammatory Response‐Specific Wound Healing

Abstract Hydrogen sulfide (H 2 S) plays crucial inflammatory modulating roles, representing a promising candidate for anti‐inflammatory therapies. However, current H 2 S delivery approaches lack sufficient specificity against inflammatory response. Herein, regarding the overexpressed aminopeptidase N (APN) at the inflammation sites, an APN‐activated self‐immolative carbonyl sulfide (COS)/H 2 S donor ( AlaCOS ) was developed for inflammatory response‐specific H 2 S delivery. The compound showed sustained H 2 S generation upon APN activation in the presence of carbonic anhydrase (CA), and the responsiveness could be well regulated by modulating the amino acid sequence. Due to the inflammatory response‐specific sustained H 2 S delivery, AlaCOS provided potent anti‐inflammatory capability, which was further validated by RNA sequencing. In vivo experiments on a full‐thickness cutaneous wound murine model also showed the strong promoting effect on wound healing, mainly due to the regulation of the inflammatory response by AlaCOS . By introducing a caged coumarin fluorophore to the molecular architecture, self‐reporting fluorescence could be generated accompanied with APN‐mediated COS/H 2 S release, which achieved the visualization of H 2 S delivery in vitro and in vivo. This work not only offers a useful tool for studying the bioactivity of H 2 S on inflammation, but also provides new insights for developing novel therapies to cope with inflammation‐associated diseases.