Mannose Oligosaccharide-Conjugated In Situ Pore-Forming Injectable Hydrogels for Rheumatoid Arthritis Treatment by Reprogramming Macrophage Extracellular Vesicles.

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes severe cartilage erosion in joints. Current treatments are limited in accessing a 3D platform that not only supports chondrocyte recovery and new cartilage matrix formation but also effectively modulates the inflammatory environment, particularly through macrophage regulation and extracellular vesicle (EV)-mediated functions. Here, an injectable hydrogel is developed incorporating mannose oligosaccharide (MOS)-modified chondroitin sulfate and hyaluronic. This hydrogel forms a porous structure in situ, supporting cell adhesion and matrix production. The MOS groups grafted onto the hydrogel bind to CD206 receptors of macrophages, selectively recruiting and regulating M2 macrophages over an extended period. These macrophages, in turn, release EVs with potent anti-inflammatory properties, which support new cartilage formation and preservation. This innovative approach addresses a critical gap in RA treatment, offering a novel, cost-effective, and efficient tissue-engineering solution with the potential to significantly improve patient outcomes and quality of life.