Artemisinin‐Loaded Core‐Shell Microspheres Modulate Histone Lactylation to Remodel the Microenvironment for Cartilage Protection in Rheumatoid Arthritis
Year: 2026
Type: article
Abstract: 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.
Source: Advanced Healthcare Materials
DOI: 10.1002/adhm.71967
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,880
OpenAlex ID: W7225634499