Pro-efferocytic heart-homing polymeric nanoparticles alleviate acute myocardial infraction injury

Background Acute myocardial infarction (AMI) has become one of the major global health burdens. The upregulation of the CD47 on apoptotic cardiomyocytes acts as a 'don't-eat-me' signal, inhibiting the clearance of apoptotic bodies (AB) by macrophages (a process known as efferocytosis) via the Signal Regulatory Protein α (SIRPα)/ SH2 Domain-Containing Phosphatase 1 (SHP1) axis, leading to extended activation of inflammation and tissue damage. However, systemic interventions targeting this axis (e.g., blunting the phosphorylation of SHP1) are constrained by potential adverse effects, such as promoting fibrosis, suppressing immunity, and interfering the protective function of the axis to avoid the phagocytosis of normal cells. Methods A poly(lactic-co-glycolic acid)@polydopamine (PLGA@PDA) nanoparticle (NP) was developed to deliver the SHP1 inhibitor TPI1 specifically to the myocardium using a cardiac homing peptide (CHP; NP-TPI1/P), as shown in Fig 1A. The function of the nanoparticle to regulate SIRPα/SHP1 signal, and promote efferocytosis were assessed using Raw264.7 macrophages and an AMI mice model established by ligation of left anterior descending artery. The cardiac targeting capability was evaluated by In vivo imaging system (IVIS). The degrees of efferocytosis were measured by the amount of AB engulfed by Raw264.7 cells or the ratio of ABs engulfed by macrophages to total ABs in hearts. Results The responsiveness of NP-TPI1/P to reactive oxygen species (ROS) and low pH was observed. Both unmodified TPI1-loaded NP (NP-TPI1) and NP-TPI1/P effectively inhibited SHP1 phosphorylation both in vitro, thereby restoring the timely clearance of apoptotic cells by macrophages (Fig 1B,C). N NP-TPI1/P showed significantly higher accumulation in the heart and reduced retention in the liver and other tissues compared to NP-TPI1 (Fig 2A,B), leading to a more pronounced reduction in the phosphorylation level of SHP1 and a restoration of the clearance rate of apoptotic bodies (Fig 2C,D). AMI mice treated with NP-TPI1/P exhibited the most significant recovery of cardiac function (based on left ventricular ejection fraction [LVEF], Fig 2E) and the smallest fibrotic area (based on Sirius Red staining, Fig 2F) on day 21. Conclusion The NP-TPI1/P acts as an innovative nanocarrier system providing a targeted approach to enhance efferocytosis in AMI, and offering a promising new avenue for improving recovery in cardiovascular diseases.