Hypoxia-Induced and Glucuronic Acid-Modified Extracellular Vesicles from Mesenchymal Stromal Cells Treat Pulmonary Arterial Hypertension by Improving Vascular Remodeling

Achieving precise delivery of extracellular vesicles (EVs) to treat pulmonary arterial hypertension (PAH) remains challenging. Here, we propose a strategy using hypoxia-induced and glucuronic acid (GA)-modified mesenchymal stromal-cell-derived EVs (MSC-EVs) to enhance their functionalities and therapeutic targeting. The hypoxia-induced EVs (Hypo-EVs) exhibit enriched exosomal signatures and display heightened inhibition of the proliferation of pulmonary arterial smooth muscle cells (PASMCs) compared to normoxic EVs (Norm-EV). We then modify Hypo-EVs by incorporating GA into their outer membrane, targeting glucose transporter-1 overexpressed on PASMCs. Our studies show that GA-EVs significantly enhance the therapeutic efficacy, both in vitro and in vivo, through improved targeted delivery to diseased PASMCs for improving vascular remodeling. Additionally, we identify miR-5119 involved in the PAH-associated calcium signaling pathway as a key contributor to GA-EVs’ superior effects. This work provides a promising strategy for PAH treatment and advances the clinical potential of MSC-EV-based therapies.

实现细胞外囊泡（extracellular vesicles, EVs）的精准递送以治疗肺动脉高压（pulmonary arterial hypertension, PAH）仍是一大挑战。本研究提出一种策略：采用低氧诱导且经葡萄糖醛酸（glucuronic acid, GA）修饰的间充质基质细胞来源细胞外囊泡（mesenchymal stromal-cell-derived EVs, MSC-EVs），以增强其功能与治疗靶向性。相较于常氧细胞外囊泡（normoxic EVs, Norm-EV），低氧诱导的细胞外囊泡（Hypo-EVs）富集了外泌体特征，并展现出更强的肺动脉平滑肌细胞（pulmonary arterial smooth muscle cells, PASMCs）增殖抑制活性。随后，我们通过在Hypo-EVs外膜结合GA对其进行修饰，靶向PASMCs上过表达的葡萄糖转运蛋白1（glucose transporter-1）。研究表明，GA-EVs可通过优化对病变PASMCs的靶向递送以改善血管重构，从而在体外与体内实验中显著提升治疗效果。此外，我们发现参与PAH相关钙信号通路的miR-5119是GA-EVs发挥优异功效的关键介导因子。本研究为PAH治疗提供了一种极具前景的策略，并提升了基于MSC-EVs的疗法的临床应用潜力。