Aminopeptidase N‐Activated Self‐immolative Hydrogen Sulfide Donor for Inflammatory Response‐Specific Wound Healing
Fan Rong, Wenxin Bao, Guanyi Li, Yuxuan Ge, Wangyang Zhu, Bin Hao, Yaxue Zhao, Yaxue Zhao, Yunsheng Yuan, Yunsheng Yuan, Yin Wang
Abstract
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.