Artemisinin‐Loaded Core‐Shell Microspheres Modulate Histone Lactylation to Remodel the Microenvironment for Cartilage Protection in Rheumatoid Arthritis

Rheumatoid arthritis (RA) involves persistent inflammation and metabolic dysregulation that jointly drive cartilage damage. Although lactate accumulates in arthritic joints, the role of lactate-induced histone lactylation in cartilage progenitor cell (CPC) dysfunction remains unclear. Here, we developed an injectable, tissue-adhesive core-shell microsphere (ART@PLGA@GH-A) for sustained intra-articular delivery of artemisinin (ART). CUT&Tag sequencing identified a pathological lactate-H4K16la-Ccnb2 axis in RA-derived CPCs, in which lactate accumulation enhanced H4K16la enrichment at the Ccnb2 promoter, promoting mitochondrial dysfunction, cellular senescence, and extracellular matrix degradation. ART@PLGA@GH-A suppressed H4K16la deposition at the Ccnb2 locus and more effectively inhibited CPC senescence and glycolytic lactate production than ART-loaded hydrogel microspheres (ART@GH). Mechanistically, ART@PLGA@GH-A promoted macrophage polarization from pro-inflammatory M1 toward anti-inflammatory M2, reduced intracellular and mitochondrial reactive oxygen species, restored mitochondrial membrane potential and dynamics, enhanced chondrogenic markers (COL II, Aggrecan, and SOX9), and reduced matrix-degrading enzymes (MMP13 and ADAMTS5). In collagen-induced arthritis rats, a single intra-articular injection of ART@PLGA@GH-A reduced subchondral bone erosion and proteoglycan loss and improved hindlimb gait function, outperforming free ART and non-adhesive microspheres. Therefore, ART@PLGA@GH-A targets the lactate-dependent H4K16la-Ccnb2 axis and restores joint homeostasis, thereby achieving synergistic anti-inflammatory, anti-senescent, and chondroprotective effects and providing a clinically translatable local therapeutic strategy for RA.