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 <i>in vitro</i> and <i>in vivo</i>, 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.