Microenvironment‐Regulated Hydrogels Prepared with a Brand‐New Small Molecule Cross‐Linker for Stepwise Treatment of Myocardial Infarction

Abstract Despite the development of many injectable hydrogels intended for the repair of myocardial infarction (MI), their effectiveness is often compromised because they target merely one or two phases of MI's pathological progression. Here, a multifunctional hydrogel delivery platform is prepared with a brand‐new small molecule cross‐linker for stepwise treatment of MI. The synthesis and reporting of a novel small‐molecule phenylboronic acid cross‐linker ((N(BA) 3 )) with a precise molecular structure is conducted for the first time, and it is successfully utilized with polyvinyl alcohol (PVA) dopamine to prepare a hydrogel with infarct microenvironmental responsiveness and anti‐oxidant. Further, considering the multistage of MI repair, hydrogel contains both hyperoside bioactive nanoparticles (EGCG@Hyp&Arg NPs) and PLGA microspheres loaded with galunisertib (PLGA@Gal Ms). The EGCG@Hyp&Arg NPs are rapidly released and demonstrate anti‐inflammatory and pro‐angiogenesis effects, while in the long term, Gal is released from the PLGA@Gal Ms to inhibit myocardial fibrosis and improve cardiac function. Results from both in vitro and in vivo studies reveal that the hydrogel is engineered with programmed capabilities for anti‐oxidation, reducing inflammation, promoting new blood vessel formation, and inhibiting fibrosis, thereby significantly enhancing heart function post‐MI. Overall, this multifunctional hydrogel delivery platform has great potential for application as a therapeutic strategy for MI.