Dendritic cell-derived exosomes as a potential immunotherapeutic strategy for ligament healing: A narrative review
Abstract
Ligament injuries remain major challenges in orthopedics and sports medicine because these tissues are hypocellular and hypovascular, often healing through biomechanically inferior fibrotic scarring. Persistent inflammation, dominated by pro-inflammatory M1 macrophages, limits effective tissue regeneration. Cell-free therapies using extracellular vesicles, especially dendritic cell-derived exosomes (DEXs), may offer a novel immunotherapeutic strategy to regulate local immune responses and promote functional ligament repair. This review synthesizes preclinical evidence on how DEXs modulate the local immune microenvironment to promote ligament and tendon-bone interface healing. A structured literature search was performed in May 2026 in PubMed/MEDLINE, Scopus, and Web of Science, combining keywords and MeSH terms for dendritic cell exosomes, ligament healing, tendon-bone interface, macrophage polarization, and the PI3K/Akt pathway. Preclinical studies, reviews of exosome-based immunotherapy for musculoskeletal tissues, and studies of macrophage polarization in ligament repair were included; conference abstracts, opinion pieces, and non-English articles were excluded. DEXs from immature or tolerogenic dendritic cells carry immunoregulatory proteins, membrane lipids, and functional miRNAs that modulate macrophage behavior. After uptake by host macrophages, DEXs promote M1-to-M2 polarization by activating the class I phosphoinositide 3-kinase/protein kinase B pathway, suppressing catabolic cytokines, enhancing tendon stem/progenitor cell migration and proliferation, supporting collagen type I synthesis, reducing disorganized collagen type III deposition, and improving ligament biomechanical recovery. Preclinical evidence indicates that cell-free immunotherapy with DEXs is a promising approach for restoring tissue homeostasis after ligament injury by guiding the transition from inflammation to regeneration. Clinical translation will require standardized large-scale isolation protocols and effective biomaterial carriers, such as fibrin sealants, for sustained local delivery.