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

IF 6.5 2区医学 Q1 NANOSCIENCE & NANOTECHNOLOGY

International Journal of Nanomedicine Pub Date : 2025-08-27 eCollection Date: 2025-01-01 DOI:10.2147/IJN.S533628

Qi Pan, Guihao Chen, Xiaoli Zhuang, Fei Li, Yuejin Yang

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引用次数: 0

Abstract

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.

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心脏归巢肽功能化聚合物纳米颗粒抑制SHP1通过促进efferocysis和抑制炎症减轻急性心肌梗死损伤。

目的：急性心肌梗死（AMI）是全球主要的健康问题。CD47在凋亡心肌细胞上的上调作为一个“不要吃我”的信号，通过信号调节蛋白α (SIRPα)/含SH2结构域磷酸酶1 （SHP1）轴抑制巨噬细胞对凋亡细胞的清除（一个称为efferocytosis的过程），导致继发性炎症激活。此外，这一过程的损伤可导致巨噬细胞向修复性M2表型极化不足。针对该轴的系统性干预受到潜在副作用的限制，如促进纤维化、抑制免疫、干扰轴的保护功能以避免正常细胞的吞噬。方法：在本研究中，开发了聚（乳酸-羟基乙酸）@聚多巴胺（PLGA@PDA）纳米颗粒系统来递送SHP1抑制剂TPI1 （NP-TPI1）。用心脏归巢肽（CHP）修饰纳米颗粒，使心脏归巢（NP-TPI1/P）。利用Raw264.7细胞和小鼠AMI模型来评估这种新型纳米系统的促红细胞生成、抗炎和心脏保护作用。结果：该新型纳米颗粒对ROS和低pH响应，在体外和体内均能有效抑制SHP1磷酸化，从而恢复巨噬细胞对凋亡细胞的及时清除。它还能促进M2极化，减少继发性炎症反应。这些工程纳米颗粒表现出增强的靶向梗死灶的能力，用chp修饰的tpi1负载纳米颗粒治疗AMI小鼠，心脏功能显著改善（AMI后第21天NP-TPI1/P vs PBS左心室射血分数[LVEF]， 49.42±1.88 vs 31.61±2.30[%]），纤维化面积减少（NP-TPI1/P vs PBS, 11.60±1.60 vs 25.48±1.98[%]）。结论：本研究为开发新型的双用途纳米药物治疗心肌梗死后提供了新的见解，并为心血管疾病中efferocytosis的临床转化提供了重要的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Nanomedicine NANOSCIENCE & NANOTECHNOLOGY-PHARMACOLOGY & PHARMACY

CiteScore

14.40

自引率

3.80%

发文量

511

审稿时长

1.4 months

期刊介绍： The International Journal of Nanomedicine is a globally recognized journal that focuses on the applications of nanotechnology in the biomedical field. It is a peer-reviewed and open-access publication that covers diverse aspects of this rapidly evolving research area. With its strong emphasis on the clinical potential of nanoparticles in disease diagnostics, prevention, and treatment, the journal aims to showcase cutting-edge research and development in the field. Starting from now, the International Journal of Nanomedicine will not accept meta-analyses for publication.