Biomimetic Targeted Nanoplatform Exerts a Combined Effect of Alleviating Calcium Overload and Scavenging ROS to Attenuate the Inflammatory Response in Myocardial Ischemia-Reperfusion Injury

The myocardial ischemia-reperfusion injury (MIRI) is an acute and serious disease with complex pathogenesis, which is intricately associated with oxidative stress, calcium overload, and inflammation. Currently, widely utilized antioxidant or anti-inflammatory strategies present challenges in effectively reversing tissue damage. In this study, a biomimetic targeted mesoporous polydopamine nanoparticle (MR/B@PM) loaded with rapamycin (RAPA) and calcium chelating agent (BAPTA-AM) was successfully constructed, and precise delivery was achieved by a platelet membrane (PM). MR/B@PM facilitated targeted delivery to cardiomyocytes (26-fold) and enhanced intracellular uptake (1.75-fold) compared to MR/B, which was mainly attributed to the natural infarct homing ability of PM and the high affinity between PM and myocardial cells. MR/B@PM significantly inhibited 85.78% of hypoxia-reoxygenation (H/R)-induced cell apoptosis and exerted favorable inhibitory effects on myocardial injury with reduced CK-MB and LDH to 7.61 and 19.43 pg/mL compared to the H/R group. It was proved that MPDA acted as a combined effect with BAPTA-AM and RAPA to inhibit cardiomyocyte apoptosis and modulate the inflammatory response by scavenging ROS and reducing calcium overload. And in the MIRI rat model, MR/B@PM has been demonstrated to significantly reduce serum levels of CK-MB and LDH, while effectively suppressing inflammatory responses. Notably, MR/B@PM effectively reduced infarct size to 19.51% and prevented cardiac remodeling caused by MIRI. This designed nanoplatform comprehensively regulated the multiple pathogenesis of MIRI, which provided an effective strategy and mechanism for the treatment of MIRI.