Smart Hydrogel Systems for Skin Fibrosis: Rational Design, Mechanisms, and Therapeutic Applications

Abstract Skin fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition and tissue remodeling following chronic injury or inflammation. Current treatments remain limited, highlighting the need for more effective therapeutic strategies. Tissue-engineered hydrogels (TEHs) have emerged as promising platforms for fibrosis intervention due to their biocompatibility and tunable physicochemical properties. This review summarizes recent advances in TEH-based approaches for skin fibrosis, with a focus on the design of smart hydrogels. Unlike conventional scaffolds, smart hydrogels can sense pathological changes in the fibrotic microenvironment and respond to disease-associated cues, including pH changes, elevated reactive oxygen species (ROS), enzymatic activity, and mechanical alterations. These adaptive systems enable controlled cargo delivery and local microenvironment regulation. We further discuss multifunctional hydrogel platforms incorporating bioactive molecules, nucleic acids, and nanomaterials to modulate key fibrotic pathways. Finally, we highlight current challenges in clinical translation and future perspectives for developing safer and more effective responsive hydrogel therapies for skin fibrosis.