Localized Delivery of Mesenchymal Stem Cell Spheroids via an Injectable Hydrogel for Rheumatoid Arthritis Therapy

Rheumatoid arthritis (RA) is an autoimmune disorder marked by chronic joint inflammation and tissue damage. While current systemic therapies mainly reduce inflammation, they often lack regenerative capacity and cause off-target effects. To address this, we developed an injectable collagen–hyaluronic acid (Col-HA-NHS) hydrogel for intra-articular delivery of umbilical mesenchymal stem cell (UMSC) spheroids. The hydrogel demonstrated excellent shear-thinning and regelable properties, biocompatibility, and controlled degradation. Encapsulated UMSC spheroids (S-UMSCs) exhibited enhanced paracrine function, secreting higher levels of growth factors such as epidermal growth factor (EGF) and fibroblast growth factor (FGF) than those of monolayer cultures. In vitro, the hydrogel–spheroid system (CH/S-UMSCs) significantly inhibited M1 macrophage polarization, as indicated by reduced CD86 expression, and decreased intracellular reactive oxygen species (ROS). In a rat collagen-induced arthritis (CIA) model, intra-articular administration of CH/S-UMSCs led to the most pronounced reduction in paw swelling and the highest clinical healing score among all groups. Histopathological and micro-CT analyses further revealed that this treatment markedly alleviated synovial inflammation, mitigated cartilage erosion, and suppressed bone destruction, while significantly improving bone mineral density (BMD) and trabecular microstructure. This combinatory strategy thus provides a synergistic therapy integrating immunomodulation and tissue regeneration, offering a promising localized treatment for RA.