Department of Cardiovascular Medicine, Heart Failure Center, Ruijin Hospital, and Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, 149 S. Chongqing Road, Shanghai, 200023, China.
Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200023, China.
Adv Mater. 2023 Nov;35(48):e2302801. doi: 10.1002/adma.202302801. Epub 2023 Oct 27.
The lesion core is the area with the most serious injury and vigorous repair. Existing nanocarriers are difficult to break through the targeted delivery to the lesion core for precise treatment in the intracellular and extracellular microenvironment. Herein, a cellular membrane-engineered nanovesicle (CMEV) with a hierarchical structure is constructed using the double emulsion-extrusion method by integrating a neutrophil membrane, functional antibody, and gelled drug-loaded core as a three-stage booster to target the lesion core and deliver catestatin (CST), a small therapeutic peptide, for ischemic cardiomyopathy therapy. By coating the neutrophil membrane outside the shell, CMEV is endowed with the function of neutrophil-like migration to achieve the first stage of tissue targeting. Based on the specific anchoring to injured myocardium, a myosin light chain 3 (MLC3) antibody is embedded to fulfill the second stage of CMEV accumulation in the lesion core. The gelled core containing CST-sodium alginate (NaAlg) with a pH-responsive shell is prepared by ionic cross-linking to accomplish the third stage of precise CST administration. Triggered by the microenvironment, NaAlg electrostatically adheres to the lesion core for sustained release, enhancing the efficacy of CST in improving cardiomyocyte apoptosis, excessive fibrosis, macrophage polarization, and angiogenesis. Thus, the "three-stage booster" nanovesicle significantly ameliorates cardiac function and adverse remodeling to treat ischemic cardiomyopathy.
病变核心是损伤最严重和修复最活跃的区域。现有的纳米载体很难突破靶向传递到病变核心，以实现细胞内和细胞外微环境的精确治疗。在此，通过双重乳液挤出法构建了一种具有层次结构的细胞膜工程化纳米囊泡（CMEV），该囊泡通过整合中性粒细胞膜、功能抗体和凝胶化载药核心作为三级助推器来靶向病变核心，并递送小治疗肽 catestatin（CST），用于治疗缺血性心肌病。通过在壳外包覆中性粒细胞膜，CMEV 被赋予了类似于中性粒细胞的迁移功能，从而实现了组织靶向的第一阶段。基于对损伤心肌的特异性锚定，嵌入肌球蛋白轻链 3（MLC3）抗体以实现 CMEV 在病变核心中的积累的第二阶段。通过离子交联制备含有 CST-海藻酸钠（NaAlg）的凝胶化核心，具有 pH 响应性外壳，以实现精确 CST 给药的第三阶段。在微环境的触发下，NaAlg 静电附着在病变核心上进行持续释放，增强了 CST 改善心肌细胞凋亡、过度纤维化、巨噬细胞极化和血管生成的功效。因此，“三级助推”纳米囊泡显著改善了心脏功能和不良重构，从而治疗缺血性心肌病。
