ROS-responsive Prussian blue nanoplatform for synergistic myocardial ischemia/reperfusion injury therapy via EGCG delivery and DJ-1 pathway regulation

Effective management of myocardial ischemia/reperfusion (I/R) injury remains a clinical challenge. Epigallocatechin gallate (EGCG), a natural antioxidant, exhibits therapeutic potential in I/R models; however, it is limited by poor bioavailability and inadequate targeted delivery. Therefore, using a synergistic therapeutic strategy, we designed a nanoplatform (PB@PEI@FPBA-EGCG NPs, referred to as PPFE NPs) to address these limitations. PPFE NPs integrate Prussian blue nanoparticles (PB NPs) with EGCG, harnessing the multi-enzyme–mimicking activities of PB NPs (SOD/CAT mimetic, •OH scavenging) together with the pharmacological properties of EGCG. Notably, in this nanoplatform, PB NPs and EGCG demonstrate excellent synergistic therapeutic effects, characterized by enhanced ROS-responsive drug release and injured cardiac tissue-selected delivery. In vitro and in vivo studies confirmed the efficacy of PPFE NPs in neutralizing ROS, restoring mitochondrial homeostasis, and inhibiting apoptosis following I/R injury. Mechanistically, cardioprotection was mediated through the regulation of DJ-1 (PARK7) and its downstream pathways—Nrf2/ARE antioxidant signaling and ASK1/p38/JNK apoptotic regulation. Importantly, this study is the first to utilize native PB NPs as an EGCG carrier, exploiting their ROS scavenging ability and boronate ester bonds to improve EGCG loading efficiency and targeted delivery. Furthermore, we innovatively found that the combination of EGCG and DJ-1 may represent a key mechanism underlying the protective effects of EGCG against myocardial ischemia/reperfusion injury (MIRI). This work pioneers a ROS-responsive Prussian blue (PB) nanoplatform with superior synergistic efficacy. The study establishes PPFE NPs as a biocompatible nano-platform for myocardial I/R injury and provides a translatable strategy to optimize the clinical application of EGCG.