Injectable bioactive glass hydrogels orchestrate metalloimmunotherapy by depleting pathogenic B cells and rescuing bone in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by persistent synovial inflammation and progressive bone destruction. Transcriptomic profiling identified hyperactivated B cells as key contributors to osteoimmune dysregulation, supporting localized B cell intervention as a therapeutic strategy. Here, an injectable thermosensitive hydroxypropyl chitin hydrogel incorporating Cu/Zn-doped bioactive glass particles, termed BG@HPCH, was developed for localized metalloimmunotherapy. BG incorporation improved the shear-thinning behavior, thermosensitive gelation, storage modulus, and stability of the hydrogel. In vitro, ionic release from BG@HPCH selectively reduced pathogenic B cell survival while preserving mesenchymal stem cell (MSC) viability. The optimized M-BG@HPCH increased the B cell dead-cell area from 1.93 ± 0.48% to 91.12 ± 0.90% at 24 h, while maintaining MSC viability at 98.59 ± 0.26% after 3 days. In TNF-transgenic mice, a single intra-articular injection of BG@HPCH reduced arthritis index scores from 2.88 ± 0.18 to 1.81 ± 0.13 at day 28, limited bone erosion, and showed no detectable systemic toxicity. Micro-CT analysis showed improved bone preservation, with BV/TV increasing from 30.00 ± 6.74% to 55.66 ± 1.07%. OCN staining further confirmed enhanced osteogenic activity, with the OCN⁺ area increasing by 2.16 times. Flow cytometry confirmed reduced B220⁺CD45.2⁺ B cell accumulation in treated joints. Single-cell RNA sequencing of 23,921 joint cells showed that BG@HPCH reduced inflammatory B cell, macrophage, and fibroblast subsets while expanding osteoblast-associated regenerative populations, accompanied by suppression of CD23^- and CD74-associated B cell signaling axes. These findings establish BG@HPCH as a localized immunoregenerative biomaterial for coordinating pathogenic B cell depletion and bone repair in RA.