Inhibition of neuron and cardiac remodeling by microenvironment-responsive injectable hydrogels with sympatho-immune regulation properties for myocardial infarction therapy

Inflammation-dominated sympathetic innervation adjacent to the infarcted region plays a pivotal role in the pathogenesis of severe ventricular arrhythmias (VAs) following myocardial infarction (MI). Thus, targeting inflammation process and sympathetic innervation represents a promising therapeutic approach to prevent VAs in clinical settings. Herein, we developed intelligent injectable hydrogels using boronic ester dynamic crosslinking as a pH- and reactive oxygen species (ROS)-responsive mechanism. We synthesized fluorophenylboronic acid-modified gelatin (GelPB) and combined it with polyvinyl alcohol (PVA) to create GelPB/PVA hydrogels (GP-gel) loaded with c-type natriuretic peptide (CNP) and Sema3A. The efficacy of this smart hydrogel was evaluated in an MI model induced by left anterior descending coronary artery ligation . The drug-loaded hydrogel demonstrated the excellent anti-inflammatory, pro-angiogenic, and anti-nerve sprouting effects. Specifically, it reduced macrophages infiltration, promoted M2 macrophage polarization in the early post-MI phase, and enhanced the expression of CD31 and a-SMA. As a result, sympathetic hyperinnervation was suppressed, arrhythmia susceptibility was reduced, and electrical conduction velocity was improved. Additionally, a notable improvement in cardiac function was observed. In conclusion, hydrogel co-loaded with CNP and Sema3A offers a promising therapeutic strategy for addressing both malignant arrhythmia and heart failure post-MI. • A smart pH- and ROS-responsive GelPB/PVA hydrogel loaded with CNP and Sema3A was developed for post-infarction repair. • CNP/Sema3A-loaded hydrogels exhibit remarkable anti-inflammatory, pro-angiogenic, and anti-nerve sprouting properties. • The hydrogel-based drug delivery platform significantly ameliorated sympathetic nerve sprouting and improved electrical conduction properties following MI. • The hydrogel loading system effectively reversed cardiac remodeling and enhanced cardiac function.