CAP-CD56+CD271+ BMSCs exos-loaded PVA/SA sustained-release hydrogel attenuates chondrocyte senescence and ameliorates lumbar facet joint osteoarthritis

This study aimed to develop a novel, targeted therapy for lumbar facet joint osteoarthritis (LFJ OA) by identifying a potent bone mesenchymal stem cell (BMSC) subpopulation for cartilage regeneration, engineering its exosomes (Exos) for specific delivery, and incorporating them into a sustained-release hydrogel system. The study also aimed to elucidate the underlying molecular mechanism.A CD56+CD271+BMSCs subpopulation with potent cartilage regeneration potential within the human bone marrow was identified through single-cell RNA sequencing and then isolated. Exos were subsequently extracted from this specific subpopulation and engineered with a chondrocyte-specific antigen peptide (CAP) to generate CAP-CD56+CD271+BMSCs Exos. A polyvinyl alcohol (PVA)/sodium alginate (SA) composite hydrogel was developed to serve as a sustained-release carrier for these targeted exosomes. Finally, the efficacy of the composite system was rigorously evaluated both in vitro and in vivo, and mechanistic insights were pursued through sequencing and molecular experiments.Compared with conventional BMSCs, the CD56+CD271+BMSCs subpopulation and its derived exosomes demonstrated significantly enhanced pro-chondrogenic and anti-senescence capabilities compared to conventional BMSCs. CAP modification substantially improved in vivo targeting efficiency to chondrocytes, whereas the PVA/SA hydrogel enabled sustained exosome release, prolonging retention at injury sites. Implantation of the integrated CAP-Exos-PVA/SA system markedly improved osteoarthritis cartilage structure, increased matrix deposition, and suppressed the expression of matrix metalloproteinase-13 (MMP-13) and senescence markers (p16/p21/p53). Mechanistic studies revealed that the Exo-mediated delivery of miR-210-3p inhibited hypoxia-inducible factor-3α (HIF-3α) expression in chondrocytes. These therapeutic effects were abolished upon miR-210-3p blockade or HIF-3α overexpression.The CAP-CD56+CD271+BMSCs Exos-PVA/SA hydrogel sustained-release system presents a promising and effective therapeutic approach for LFJ OA.Image 1View The PDF