In Situ Synthesis of Glycosaminoglycan‐Mimicking Coatings Driven by Local Pathological Microenvironment: Boosting Bladder Mucosal Regeneration and Barrier Function

ABSTRACT The development of assembly interfaces that emulate subcellular chemical communication at the biotic‐abiotic interface is a central pursuit in synthetic biology. However, engineering in situ self‐assembling systems that combine robust retention against mucosal flushing and microenvironmental regulatory functions remains a formidable challenge. Herein, we present an intravesical in situ synthetic strategy that exploits endogenous microenvironmental triggers to construct a glycosaminoglycan (GAG)‐mimetic coating for durable mucosal repair. By leveraging catalase (CAT) and hydrogen peroxide (H 2 O 2 ) inherent to inflammatory microenvironments, we drive the polymerization of alginate oligosaccharide‐conjugated polydopamine (AOS‐PDA). The resulting coating recapitulates the anionic and barrier properties while exhibiting anti‐inflammatory activity. In rat models of cyclophosphamide (CYP)‐induced interstitial cystitis, AOS‐PDA treatment significantly restored urothelial barrier integrity, reduced vascular permeability, and alleviated bladder dysfunction. Histological and molecular analyses confirmed the attenuation of inflammation, characterized by decreased mast cell infiltration and downregulation of key inflammatory mediators. Furthermore, the coating demonstrated sustained retention for up to three days post‐administration. These findings highlight a bio‐responsive, endogenous enzyme‐driven approach to synthesizing functional GAG‐like interfaces, offering a versatile therapeutic platform for broader mucosal repair applications.