Injectable Microenvironment-Responsive Hydrogel for Local Procyanidin B2 Delivery and Cardiac Ischemia–Reperfusion Repair

Myocardial ischemia-reperfusion (IR) injury is a key pathological process that causes adverse outcomes following revascularization in acute myocardial infarction. This process is mainly driven by mitochondrial dysfunction, oxidative stress, and inflammatory cascades. Although procyanidin B2 (PCB2), a natural polyphenol, exhibits strong antioxidant and anti-inflammatory properties, its clinical use remains limited due to poor targeting, unfavorable pharmacokinetics, and oxidative instability. Herein, we developed a dual pH- and reactive oxygen species-responsive hydrogel (poly(vinyl alcohol)–TSPBA [N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1,N1,N3,N3-teramethylpropane-1,3-diaminium]) using phenylboronic acid ester cross-linking to enable the microenvironment-responsive, on-demand release of PCB2. Dynamic rheology, scanning electron microscopy, and degradation assays confirmed the hydrogel’s excellent mechanical properties and responsiveness to microenvironmental changes. In vitro experiments demonstrated that the PCB2-loaded hydrogel effectively scavenged DPPH radicals and H2O2 while substantially reducing oxidative damage in H9C2 cardiomyocytes. Mechanistically, PCB2 may reduce NRF2 ubiquitination-mediated degradation, thereby modulating the KEAP1-NRF2 pathway to activate downstream antioxidant response elements and restore mitochondrial membrane potential. Additionally, PCB2 reversed lipopolysaccharide- and interferon-γ-induced M1 macrophage polarization, inhibited nuclear factor κB phosphorylation, and reduced the secretion of pro-inflammatory cytokines. Following intramyocardial injection of the PCB2-loaded hydrogel in a rat IR model, oxidative stress was significantly reduced, cardiac function was improved, infarct size was diminished, and fibrotic remodeling was inhibited. Transmission electron microscopy confirmed the restoration of mitochondrial cristae integrity. This study provides evidence for a synergistic multimodal approach that combines mitochondrial protection, antioxidant defense, and anti-inflammatory modulation, supported by comprehensive validation across material design, molecular mechanisms, and therapeutic efficacy. Our findings contribute to the advancement of a microenvironment-adaptive nanotherapeutic paradigm for precision intervention in myocardial IR injury.