Guo Wenjie, Chen Huiming, Liu Fengjiao, Chen Boliang, Liu Canzhao, Cai Yanbin
Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Department of Cardiology and Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Department of Cardiology and Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; Center for Translational Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
J Control Release. 2025 Feb 10;378:719-734. doi: 10.1016/j.jconrel.2024.12.042. Epub 2024 Dec 28.
Myocardial ischemia-reperfusion (I/R) injury represents a significant clinical challenge with limited therapeutic options. Single-cell RNA sequencing and bioinformatics analyses have revealed complex cellular interactions within cardiac tissue, highlighting the crucial role of cardiomyocytes in intercellular communication. During I/R injury, cardiomyocytes experience severe endoplasmic reticulum (ER) stress, leading to detrimental intercellular communication that affects surrounding cells, particularly promoting the transformation of macrophages toward a pro-inflammatory phenotype. This amplifies the inflammatory cascade and exacerbates tissue damage. Targeting injured cardiomyocytes and inhibiting their ER stress presents a promising therapeutic strategy to restore beneficial intercellular communication and maintain myocardial homeostasis, thereby reducing I/R injury. However, the lack of an effective ER stress inhibitor specifically targeting damaged cardiomyocytes constitutes a major barrier to translating mechanistic understanding into therapeutic implementation. Peptide amphiphiles (PA), with their unique amphiphilicity and bioactive functions, constitute ideal candidates for targeted drug delivery. In this study, we developed a cascade-responsive drug delivery system, CT-PA@Sal, which selectively targets damaged cardiomyocytes and controls the release of the ER stress inhibitor Salubrinal. CT-PA@Sal demonstrates superior targeting efficiency and enhanced drug bioavailability, enabling responsive release within injured cardiomyocytes. In vitro and in vivo experiments further show that CT-PA@Sal improves cardiomyocyte-macrophage communication, reduces cardiomyocyte apoptosis, and promotes anti-inflammatory M2 macrophage polarization. These effects preserve cardiac function and enhance tissue recovery following I/R injury. We envision that this investigation offers a prospective framework for developing targeted drugs to treat myocardial I/R injury.
心肌缺血再灌注（I/R）损伤是一项重大的临床挑战，治疗选择有限。单细胞RNA测序和生物信息学分析揭示了心脏组织内复杂的细胞间相互作用，突出了心肌细胞在细胞间通讯中的关键作用。在I/R损伤期间，心肌细胞会经历严重的内质网（ER）应激，导致有害的细胞间通讯，影响周围细胞，特别是促进巨噬细胞向促炎表型转变。这会放大炎症级联反应并加剧组织损伤。靶向受损心肌细胞并抑制其内质网应激是一种有前景的治疗策略，可恢复有益的细胞间通讯并维持心肌稳态，从而减少I/R损伤。然而，缺乏专门针对受损心肌细胞的有效内质网应激抑制剂是将机制理解转化为治疗应用的主要障碍。肽两亲分子（PA）具有独特的两亲性和生物活性功能，是靶向药物递送的理想候选物。在本研究中，我们开发了一种级联响应药物递送系统CT-PA@Sal，它选择性地靶向受损心肌细胞并控制内质网应激抑制剂Salubrinal的释放。CT-PA@Sal表现出卓越的靶向效率和增强的药物生物利用度，能够在受损心肌细胞内进行响应性释放。体外和体内实验进一步表明，CT-PA@Sal改善了心肌细胞与巨噬细胞之间的通讯，减少了心肌细胞凋亡，并促进了抗炎性M2巨噬细胞极化。这些作用维持了心脏功能并增强了I/R损伤后的组织恢复。我们设想，这项研究为开发治疗心肌I/R损伤的靶向药物提供了一个前瞻性框架。
