Functionalized Hydrocaffeic acid-Chitosan/EGTA Hydrogel Rescues Mitochondrial Dysfunction for Immunomodulation and Joint Repair in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by progressive joint degradation, with mitochondrial dysfunction significantly contributing to its pathogenesis. Despite extensive research into therapeutic strategies, successfully addressing mitochondrial dysfunction in RA poses a significant challenge. This paper presents an innovative functionalization method, deploying hydrocaffeic acid-modified chitosan, in conjunction with the selective calcium chelator ethylene glycol bis(β-aminoethyl ether)-N,N,N’,N’-tetraacetic acid (EGTA), and incorporating stromal cell-derived factor 1 alpha (SDF-1α). In vitro , this functionalized hydrogel exhibited a significant decrease in intracellular reactive oxygen species (ROS) levels, stabilization of mitochondrial membrane potential, mitigation of calcium overload, inhibition of mitochondrial dysfunction-induced cellular senescence, and a reduction in the release of senescence-associated secretory phenotype components. In vivo , this hydrogel effectively modulated immune responses and aided cartilage repair in a collagen-induced arthritis rat model. From a mechanistic perspective, high-throughput sequencing suggests that the therapeutic efficacy of this hydrogel may be associated with its ability to modulate mitochondrial function and inflammatory pathways. In summary, the hydrocaffeic acid- and EGTA-based functionalization strategy provides an innovative and straightforward process for integrating multiple functionalities into a single delivery platform, demonstrating the potential for tissue regeneration applications extending beyond RA.