Controlled release of hypoxic exosomes from PLGA microspheres attenuates IVDD progression through activating PPAR-γ and suppressing oxidative stress-mediated NPCs senescence

Oxidative stress and apoptosis mediated senescence of nucleus pulposus cells (NPCs) and the degradation of extracellular matrix (ECM), which represent a key mechanism underlying intervertebral disc degeneration (IVDD). Mesenchymal stem cell-derived exosomes hold therapeutic potential for tissue repair; however, their clinical application is limited by rapid clearance, short half-life, and poor target specificity. To overcome these challenges, this study developed poly(lactic-co-glycolic acid) (PLGA) microspheres as a sustained-release carrier for exosomes derived under either normoxic (Exos, 21% O₂) or hypoxic (H-Exos, 1% O₂) conditions. The PLGA microspheres demonstrated high exosome-loading efficiency and provided controlled release for over four weeks. Released hypoxic exosomes activate PPAR-γ pathway, exerting better effects by reducing NPCs SA-β-gal positive rate by 59.8% and elevates Col II and ACAN levels by 30.7% and 25.5%. Animal experiments confirmed that this system effectively attenuated IVDD progression indicating its potential for clinical translation. • Fabricated PLGA microspheres with > 90 % exosome encapsulation efficiency and 4-week controlled release capability. • Hypoxic exosomes significantly enhance the cell activities of NPCs by reducing the SA-β-gal positive rate with 59.8 %. • PLGA@H-Exos antagonize oxidative stress and reduce ROS levels with 61.5 %. • Hypoxic preconditioning enhances the bioactivity of exosomes in activating the PPAR-γ pathway by enriching HIF-1α.