Future perspectives on mesenchymal stromal cell-derived secretomes in knee osteoarthritis

Knee osteoarthritis (OA) represents a progressive degenerative joint disorder characterized by articular cartilage degradation, chronic synovial inflammation, and pathological subchondral bone remodeling. Despite its prevalence and substantial socioeconomic impact, current therapeutic strategies remain predominantly symptomatic, failing to address the underlying disease mechanisms. Mesenchymal stromal cells (MSCs) have emerged as promising therapeutic agents, with accumulating evidence suggesting their efficacy stems primarily from paracrine signaling rather than direct cellular differentiation. The MSC-derived secretome, comprising extracellular vesicles (particularly exosomes), growth factors, cytokines, and immunomodulatory proteins, represents a sophisticated cell-free therapeutic platform capable of simultaneously targeting multiple pathological pathways in OA. This narrative review synthesizes current knowledge regarding the molecular mechanisms through which MSC-derived secretomes modulate the OA microenvironment, critically analyzes preclinical and emerging clinical evidence, and addresses the formidable challenges confronting clinical translation. We examine the secretome’s role in chondroprotection, immunomodulation, and subchondral bone homeostasis, while identifying critical gaps in standardization, delivery optimization, and regulatory frameworks that must be addressed to realize the full therapeutic potential of this promising regenerative strategy.