Clinical-grade extracellular vesicles derived from umbilical cord mesenchymal stromal cells: preclinical development and first-in-human intra-articular validation as therapeutics for knee osteoarthritis

作者：Aliosha I. Figueroa‐Valdés, Patricia Luz‐Crawford, Yeimi Herrera-Luna, Nicolás Georges-Calderón, Cynthia García, Hugo E. Tobar, Munemitsu Araya, José Matas, Darío Donoso-Meneses, Catalina de la Fuente, Jimena Cuenca, Eliseo Parra, Fernando Lillo, Cristina Rodríguez-Varela, María Ignacia Cádiz, Rolando Vernal, Alexander Ortloff, Gino Nardocci, Verónica Castañeda, Catalina Adasme-Vidal, Maximiliano Kunze-Küllmer, Yessia Hidalgo, Francisco Espinoza, Maroun Khoury, Francisca Alcayaga‐Miranda · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-024-03088-x · 被引用次数：60 · 研究领域：Extracellular vesicles in disease、Osteoarthritis Treatment and Mechanisms、Bone and Joint Diseases

Osteoarthritis (OA) is a joint disease characterized by articular cartilage degradation. Persistent low-grade inflammation defines OA pathogenesis, with crucial involvement of pro-inflammatory M1-like macrophages. While mesenchymal stromal cells (MSC) and their small extracellular vesicles (sEV) hold promise for OA treatment, achieving consistent clinical-grade sEV products remains a significant challenge. This study aims to develop fully characterized, reproducible, clinical-grade batches of sEV derived from umbilical cord (UC)-MSC for the treatment of OA while assessing its efficacy and safety. Initially, a standardized, research-grade manufacturing protocol was established to ensure consistent sEV production. UC-MSC-sEV characterization under non-cGMP conditions showed consistent miRNA and protein profiles, suggesting their potential for standardized manufacturing. In vitro studies evaluated the efficacy, safety, and potency of sEV; animal studies confirmed their effectiveness and safety. In vitro, UC-MSC-sEV polarized macrophages to an anti-inflammatory M2b-like phenotype, through STAT1 modulation, indicating their potential to create an anti-inflammatory environment in the affected joints. In silico studies confirmed sEV's immunosuppressive signature through miRNA and proteome analysis. In an OA mouse model, sEV injected intra-articularly (IA) induced hyaline cartilage regeneration, validated by histological and μCT analyses. The unique detection of sEV signals within th...