Targeting CXCL16-expressing macrophages with a biomimetic nanocarrier system attenuates cartilage degeneration in osteoarthritis

Osteoarthritis (OA) is a whole-joint disorder characterized by progressive cartilage degradation and chronic synovial inflammation, in which macrophages play a central role. Using single-cell RNA Sequencing of human and mouse synovial tissues, we identified a pronounced expansion of macrophages during OA progression, with nearly ubiquitous expression of the chemokine CXCL16. These CXCL16⁺ macrophages exhibited a pro-inflammatory phenotype and were strongly associated with synovitis. To exploit this target, we developed a biomimetic nanoparticle (MAP6) by coating capsaicin-loaded poly(lactic-co-glycolic acid) (PLGA) with CXCR6-enriched M1 macrophage membranes, leveraging the specific CXCL16-CXCR6 interaction. The resulting MAP6 nanoparticles demonstrated enhanced cellular uptake, prolonged synovial retention, and specific targeting of CXCL16⁺ macrophages in vivo. Furthermore, MAP6 treatment promoted CA²⁺ influx and NRF2 nuclear translocation, thereby suppressing pro-inflammatory cytokine expression. In a murine OA model, intra-articular administration of MAP6 markedly alleviated synovitis, reduced cartilage degradation, and suppressed the expression of catabolic factors. Collectively, this study highlights CXCL16 as a key macrophage-associated marker in OA and presents a targeted nanotherapeutic strategy capable of modulating synovial inflammation and halting disease progression.