Harnessing the gut–immune–joint axis: Oral microalgae-based thermoresponsive microspheres enhance intra-articular therapy for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease primarily caused by an aberrant immune response that erroneously attacks the synovial joints, leading to inflammation and joint damage. Emerging evidence suggests that impaired intestinal barrier integrity and imbalanced gut microbiota play crucial roles in driving RA development, promoting systemic inflammation, and exacerbating joint pathology. Here we propose a synergistic therapeutic strategy that concurrently addresses both the systemic gut-immune axis and local joint inflammation. This approach integrates intra-articular injection of triamcinolone acetonide (TAA) with oral administration of thermoresponsive microspheres encapsulating Chlorella vulgaris (CV) and ginseng polysaccharides (GPS), designated as CG@GelMA. The microspheres undergo temperature-induced gelation at body temperature, thereby facilitating gastric transit and enabling prolonged drug release in the intestinal tract. Oral administration of CG@GelMA restored intestinal barrier function by enhancing tight junction protein expression and exerting anti-inflammatory effects, while intra-articular TAA synergistically alleviated synovial inflammation, improved locomotor function, and preserved bone and cartilage integrity. Moreover, the combination therapy elicited superior immune modulation, characterized by increased regulatory T cells, reduced Th17 cells, and a systemic cytokine shift toward elevated interleukin-10 and reduced interleukin-17. Notably, this systemic immunomodulation was driven by CG@GelMA-mediated remodeling of the gut ecosystem, which enriched beneficial taxa (e.g., Lactobacillus ), reduced potentially pathogenic genera (e.g., Escherichia–Shigella ), and, importantly, led to a significant increase in the intestinal levels of immunomodulatory metabolites, including several short-chain fatty acids (SCFAs). Fecal microbiota transplantation (FMT) and depletion studies definitively established the gut microbiota as the central mediator of these therapeutic effects. Together, these findings highlight a synergistic combinatorial strategy that couples microbiota-driven systemic immunomodulation with potent local anti-inflammatory effects, offering a promising avenue for the treatment of RA and other systemic inflammatory disorders. • Thermoresponsive microspheres (CV/GPS@GelMA) deliver Chlorella vulgaris and ginseng polysaccharides to intestine for RA. • The system boosts intestinal barrier function via tight junction upregulation, reduced oxidative stress and gut inflammation. • With intra-articular triamcinolone acetonide, it eases joint inflammation, preserves bone and boosts mobility in RA mice. • Gut microbiota remodeling (increased Ligilactobacillus , decreased pathogens) mediates systemic immunomodulatory effects. • Fecal microbiota transplantation verifies gut microbiota’s key role in the combined treatment’s therapeutic effects.