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

## TL;DR

A new injectable hydrogel is developed to treat rheumatoid arthritis by recruiting anti-inflammatory macrophages and promoting cartilage repair.

## Contribution

The hydrogel uses mannose oligosaccharides to modulate macrophages and their extracellular vesicles for joint repair.

## Key findings

- The hydrogel forms a porous structure in situ, supporting cell adhesion and matrix production.
- Mannose oligosaccharides on the hydrogel bind to macrophage CD206 receptors, promoting M2 polarization.
- EVs from M2 macrophages exhibit anti-inflammatory effects and support cartilage regeneration.

## 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.

Design of an injectable porous hydrogel modulating macrophages and their secreted EVs for joint defect repair in the pathology of rheumatoid arthritis. a) The solution containing HA and CS‐MOS, upon mixing with a crosslinker solution, undergoes porous hydrogel formation with the escape of generated CO₂ gas. b) Following in situ formation of the hydrogel at the joint defect site in RA rats, the hydrogel effectively recruits macrophages and directs their polarization toward the anti‐inflammatory M2 phenotype. The EVs released by these M2 macrophages then engage with damaged chondrocytes, promoting cartilage regeneration and accelerating defect repair.