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

Hydrogen sulfide (HS) plays crucial inflammatory modulating roles, representing a promising candidate for anti-inflammatory therapies. However, current HS 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)/HS donor (AlaCOS) was developed for inflammatory response-specific HS delivery. The compound showed sustained HS 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 HS 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/HS release, which achieved the visualization of HS delivery in vitro and in vivo. This work not only offers a useful tool for studying the bioactivity of HS on inflammation, but also provides new insights for developing novel therapies to cope with inflammation-associated diseases.