A Sequential Dual Functional Supramolecular Hydrogel with Promoted Drug Release to Scavenge ROS and Stabilize HIF‐1α for Myocardial Infarction Treatment

Abstract Myocardial infarction (MI) has a characteristic inflammatory microenvironment due to the overproduction of reactive oxygen species (ROS) and causes the extraordinary deposition of collagen and thereby fibrosis. An on‐demand adaptive drug releasing hydrogel is designed to modulate the inflammatory microenvironment and inhibit cardiac fibroblasts (CFs) proliferation post MI by scavenging the overproduced ROS and releasing 1,4‐dihydrophenonthrolin‐4‐one‐3‐carboxylic acid (DPCA) to maintain the expression of hypoxia‐inducible factor 1α (HIF‐1α). DPCA is prefabricated to a prodrug linked with disulfide bond (DPCA‐S‐S‐OH). The DPCA‐S‐S‐OH and carboxylated calixarene (CSAC4A) are grafted onto the backbone of methacrylated hyaluronic acid (HAMA) to obtain HAMA‐S‐S‐DPCA and HAMA‐CA, respectively, which are further reacted to form a dual network hydrogel (R + /DPCA(CA)) with covalent linking and host–guest interaction between DPCA and CSAC4A. The ROS‐triggered hydrolysis of ester bond and subsequently sustaining release of DPCA from the cavity of CSAC4A jointly cause the constant expression of HIF‐1α, which significantly restricts the CFs proliferation, leading to suppressed fibrosis and promoted heart repair.