Work

EXO/hydrogel system for sequential regulation of endogenous hyaline cartilage regeneration

Year: 2025

Type: article

Abstract: Articular cartilage repair remains a clinically significant challenge due to its limited regenerative capacity and vulnerability to inflammation-induced damage and fibrocartilage formation. Current therapeutic strategies frequently fail to enhance intrinsic repair capacity or overcome the dual barriers of injury/inflammation-driven fibrosis and insufficient hyaline cartilage regeneration, often yielding suboptimal outcomes. Here, we developed an exosome-integrated hydrogel system for temporally programmed drug delivery. Kartogenin (KGN) and halofuginone (HF) were encapsulated into human umbilical cord MSC-derived exosomes (EXO KGN /EXO HF ). EXO HF was specifically immobilized in GelMA hydrogel via CP05-CD63 binding, while EXO KGN was incorporated unbound. This design achieved rapid release of EXO KGN versus sustained retention of EXO HF for sequential therapeutic action. The rapidly released EXO KGN initiated bone marrow-derived mesenchymal stem cell (BMSC) migration and chondrogenic differentiation in the repair process. Concurrently, the sustained release of EXO HF demonstrated anti-inflammatory and anti-fibrotic effects during later regenerative phases. This sequential release profile—first promoting BMSC recruitment and chondrogenesis, then suppressing inflammation and fibrocartilage formation—synergistically enhanced hyaline cartilage repair. Importantly, we identified that HF dynamically modulates inflammatory chemokines through the cGAS-STING pathway, maintaining a pro-regenerative microenvironment. In conclusion, our exosomal dual-drug hydrogel with sequential release successfully coordinated chondrogenesis promotion and inflammation/fibrosis suppression, significantly enhancing hyaline cartilage regeneration. Also revealed was HF’s cGAS-STING immunomodulatory mechanism, demonstrating strong potential for clinical translation. • Unique temporally programmed dual-exosome hydrogel system • Elucidation of halofuginone’s innovative immunomodulatory mechanism via cGAS-STING • Precisely timed dual-drug delivery realizing hyaline-specific chondrogenesis

Source: Materials Today Bio

DOI: 10.1016/j.mtbio.2025.102598