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

Hydrogen sulfide (H₂S) plays crucial inflammatory modulating roles, representing a promising candidate for anti-inflammatory therapies. However, current H₂S 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)/H₂S donor (AlaCOS) was developed for inflammatory response-specific H₂S delivery. The compound showed sustained H₂S 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 H₂S 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/H₂S release, which achieved the visualization of H₂S delivery in vitro and in vivo. This work not only offers a useful tool for studying the bioactivity of H₂S on inflammation, but also provides new insights for developing novel therapies to cope with inflammation-associated diseases.