Rao Zhiheng, Tang Yuli, Zhu Jiamei, Lu Zhenzhen, Chen Zhichao, Wang Jiaojiao, Bao Yuxuan, Mukondiwa Alan Vengai, Wang Cong, Wang Xiaojie, Luo Yongde, Li Xiaokun
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Oujiang Laboratory, Wenzhou 325000, China.
Nanomaterials (Basel). 2025 Feb 23;15(5):346. doi: 10.3390/nano15050346.
Acute myocardial infarction, a leading cause of death globally, is often associated with cardiometabolic disorders such as atherosclerosis and metabolic syndrome. Metabolic treatment of these disorders can improve cardiac outcomes, as exemplified by the GLP-1 agonist semaglutide. Fibroblast growth factor 21 (FGF21), a novel metabolic regulator, plays pivotal roles in lipid mobilization and energy conversion, reducing lipotoxicity, inflammation, mitochondrial health, and subsequent tissue damage in organs such as the liver, pancreas, and heart. Here, we test the therapeutic efficacy of FGF21 in mice with ischemia-reperfusion (I/R) injury, a model of acute myocardial infarction. We employed the strategic method of coating the FGF21-encapsulating liposomal nanoparticles with a neutrophil membrane designed to camouflage FGF21 from macrophage-mediated efferocytotic clearance and promote its targeted accumulation at I/R foci due to the inherent neutrophilic attraction to the inflammatory site. Our findings revealed that the coated FGF21 nanoparticles markedly accumulated within the lesions with a prolonged half-life, in additional to the liver, leading to substantial improvements in cardiac performance by enhancing mitochondrial energetic function and reducing oxidative stress, inflammation, and cell death. Therefore, our research highlights a viable strategy for the enhanced delivery of therapeutical FGF21 analogs to lesions beyond the liver following myocardial infarction.
急性心肌梗死是全球主要的死亡原因之一，常与动脉粥样硬化和代谢综合征等心脏代谢紊乱相关。对这些疾病的代谢治疗可以改善心脏预后，如GLP-1激动剂司美格鲁肽所示。成纤维细胞生长因子21（FGF21）是一种新型代谢调节剂，在脂质动员和能量转换中起关键作用，可降低脂毒性、炎症反应、改善线粒体健康，并减少肝脏、胰腺和心脏等器官随后的组织损伤。在此，我们测试FGF21对缺血再灌注（I/R）损伤小鼠（急性心肌梗死模型）的治疗效果。我们采用了一种策略性方法，即用嗜中性粒细胞膜包裹载有FGF21的脂质体纳米颗粒，该膜旨在使FGF21免受巨噬细胞介导的胞葬清除作用，并由于嗜中性粒细胞对炎症部位的固有吸引力而促进其在I/R病灶处的靶向积累。我们的研究结果表明，包被的FGF21纳米颗粒除了在肝脏中积累外，还能在病灶内显著积累，半衰期延长，通过增强线粒体能量功能、减少氧化应激、炎症反应和细胞死亡，使心脏功能得到实质性改善。因此，我们的研究突出了一种可行的策略，可增强治疗性FGF21类似物在心肌梗死后向肝脏以外病灶的递送。
