ROS-responsive hydrogel patch orchestrating macrophage reprogramming and mitochondrial protection for post-MI repair

Myocardial infarction (MI) leads to irreversible cardiomyocyte loss accompanied by oxidative stress, inflammation, and fibrotic remodeling, ultimately progressing to heart failure. Using network pharmacology analysis, salvianolic acid B (DB), a major bioactive component of <i>Salvia miltiorrhiza</i>, was identified as a promising therapeutic candidate for MI. Oral administration of DB showed therapeutic efficacy in functional, molecular, and histological assessments, but its clinical translation is limited by poor bioavailability. To overcome this limitation, we developed an injectable reactive oxygen species (ROS)-responsive hydrogel patch for localized MI repair. The hydrogel, composed of whey protein isolate methacrylate (WPI-MA) and o-nitrobenzyl alcohol modified hyaluronic acid (HA-NB), forms a biocompatible and adhesive network through dynamic covalent interactions. ROS-sensitive liposomes encapsulating DB were incorporated into the hydrogel, enabling localized and on-demand drug release in response to the oxidative microenvironment. <i>In vitro</i> studies confirmed that the hydrogel exhibited favorable mechanical strength, selective myocardial adhesiveness, and sustained antioxidant capacity. In a murine MI model, a single administration of the hydrogel patch markedly attenuated fibrosis, promoted angiogenesis, and restored cardiac function. This study establishes a rational design strategy that begins with network pharmacology-based drug discovery, proceeds through validation of therapeutic efficacy, and culminates in the construction of a responsive delivery system, providing a promising approach for localized and sustained post-infarction cardiac repair.