Cardiac Homing Peptide-Functionalized Polymeric Nanoparticles Suppressing SHP1 Alleviate Acute Myocardial Infarction Injury by Promoting Efferocytosis and Inhibiting Inflammation.

Purpose: Acute myocardial infarction (AMI) is a major global health concern worldwide. The upregulation of the CD47 on apoptotic cardiomyocytes acts as a "don't-eat-me" signal, inhibiting the clearance of apoptotic cells by macrophages (a process known as efferocytosis) via the Signal Regulatory Protein α (SIRPα)/ SH2 Domain-Containing Phosphatase 1 (SHP1) axis, leading to secondary inflammatory activation. Additionally, impairment of this process can result in insufficient macrophage polarization towards the reparative M2 phenotype. Systemic interventions targeting this axis are constrained by potential adverse effects such as promoting fibrosis, suppressing immunity, and interfering with the protective function of the axis to avoid phagocytosis of normal cells. Methods: In this study, a poly(lactic-co-glycolic acid)@Polydopamine (PLGA@PDA) nanoparticle system was developed to deliver the SHP1 inhibitor TPI1 (NP-TPI1). The nanoparticle was modified with cardiac homing peptide (CHP) to enable heart homing (NP-TPI1/P). Raw264.7 cells and mouse AMI models were utilized to assess the pro-efferocytic, anti-inflammatory, and cardioprotective effects of the novel nanosystem. Results: This novel nanoparticle, which is responsive to ROS and low pH, effectively inhibited SHP1 phosphorylation both in vitro and in vivo, thereby restoring timely clearance of apoptotic cells by macrophages. It also promotes M2 polarization and reduces the secondary inflammatory response. These engineered nanoparticles exhibited an enhanced capability to target infarcted lesions, and AMI mice treated with CHP-modified TPI1-loaded nanoparticles showed significantly improved cardiac performance (left ventricular ejection fraction [LVEF] of NP-TPI1/P vs PBS, 49.42±1.88 vs 31.61±2.30 [%] at day 21 post-AMI) and reduced fibrotic area (NP-TPI1/P vs PBS, 11.60±1.60 vs 25.48±1.98 [% of left ventricular]). Conclusion: This study provides new insights into the development of novel, dual-purpose nanomedicines for post-myocardial infarction, and holds significant potential for the clinical translation of efferocytosis in cardiovascular diseases.