Native Chemical Ligation-Driven Formation of Hyaluronic Acid-Based Injectable Hydrogels

Abstract We report the development of an injectable hyaluronic acid (HA)-based hydrogel using native chemical ligation (NCL) as a biocompatible and chemoselective crosslinking strategy for potential biomedical applications. High-molecular-weight HA was pre-modified with a glycinyl thioester derivative, while a bis-cysteine peptide served as the crosslinker, enabling rapid hydrogel formation under physiological conditions. After optimization of NCL parameters, the resulting hydrogel exhibits all key attributes for biomedical hydrogel injectables: cytocompatibility, injectability, tunable rheology adapted for soft-tissue delivery (e.g., skin and subcutaneous tissue), enzymatic degradability by hyaluronidase, adjustable swelling, and long-term shelf-life stability. It can be sterilized by autoclaving for injection purposes and also functions as a drug delivery matrix for localized, in situ release. This study presents a robust and scalable HA-based platform, available as either an injectable hydrogel or an in situ cross-linkable solution, with broad potential in drug delivery, regenerative medicine, and aesthetic applications.