Innovative hydrogel-based therapies for ischemia-reperfusion injury： bridging the gap between pathophysiology and treatment

Ischemia-reperfusion injury (IRI) commonly occurs in clinical settings, particularly in medical practices such as organ transplantation, cardiopulmonary resuscitation, and recovery from acute trauma, posing substantial challenges in clinical therapies. Current systemic therapies for IRI are limited by poor drug targeting, short efficacy, and significant side effects. Owing to their exceptional biocompatibility, biodegradability, excellent mechanical properties, targeting capabilities, controlled release potential, and properties mimicking the extracellular matrix (ECM), hydrogels not only serve as superior platforms for therapeutic substance delivery and retention, but also facilitate bioenvironment cultivation and cell recruitment, demonstrating significant potential in IRI treatment. This review explores the pathological processes of IRI and discusses the roles and therapeutic outcomes of various hydrogel systems. By categorizing hydrogel systems into depots delivering therapeutic agents, scaffolds encapsulating mesenchymal stem cells (MSCs), and ECM-mimicking hydrogels, this article emphasizes the selection of polymers and therapeutic substances, and details special crosslinking mechanisms and physicochemical properties, as well as summarizes the application of hydrogel systems for IRI treatment. Furthermore, it evaluates the limitations of current hydrogel treatments and suggests directions for future clinical applications.