Prussian Blue Nanozyme Featuring Enhanced Superoxide Dismutase-like Activity for Myocardial Ischemia Reperfusion Injury Treatment

The blood flow, when restored clinically following a myocardial infarction (MI), disrupts the physiological and metabolic equilibrium of the ischemic myocardial area, resulting in secondary damage termed myocardial ischemia-reperfusion injury (MIRI). Reactive oxygen species (ROS) generation and inflammatory reactions stand as primary culprits behind MIRI. Current strategies focusing on ROS-scavenging and anti-inflammatory actions have limited remission of MIRI. Prussian blue nanozyme (PBNz) exhibits multiple enzyme-like activities including catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD), which are beneficial for ROS clearance and fighting inflammation. Herein, a formulation of PBNz coated with polydextrose-sorbitol carboxymethyl ether (PBNz@PSC) was developed to enhance its efficacy, biocompatibility, and safety for the treatment of MIRI. PBNz@PSC not only showed enhanced SOD-like activity due to its polysaccharide attributes but also could passively target the damaged myocardium through the enhanced permeability and retention (EPR) effect. Both in vitro and in vivo studies have validated their excellent biocompatibility, safety, ROS-scavenging ability, and capacity to drive macrophage polarization from M1 toward M2, thereby diminishing the levels of IL-1β, IL-6, and TNF-α to combat inflammation. Consequently, PBNz@PSC can reverse ischemia reperfusion-induced myocardial injury, reduce coronary microvascular obstruction (MVO), and improve myocardial remodeling and cardiac function. Moreover, PBNz@PSC showed more pronounced therapeutic effects for MIRI than a clinical drug, sulfotanshinone IIA sodium. Notably, our findings revealed the possible mechanism of PBNz@PSC in treating MIRI, which mediated AMPK activation. In conclusion, this study presents a pioneering strategy for addressing MIRI, promising improved ischemia-reperfusion outcomes.