An engineering-reinforced hypoxia-preconditioned exosome-integrated hydrogel delays intervertebral disc degeneration via the PPARγ-autophagy axis

The local delivery of exosomes (Exo) through hydrogels is considered an effective method for treating intervertebral disc degeneration (IVDD). Based on the limitations of the hypoxic microenvironment in intervertebral disc (IVD), this study adopted a series of engineering methods to enhance the therapeutic efficacy of Exo and achieve sustained release effects. Specifically, by applying hypoxic preconditioning (HP), we strengthened the ability of Exo to induce extracellular matrix (ECM) synthesis and anti-apoptotic effects in nucleus pulposus cells and annulus fibrosus cells within inflammatory microenvironments, while simultaneously encapsulating them in a collagen methacrylate (COMA) hydrogel to mimic the native physiological state of IVD and achieve optimal therapeutic outcomes. HP-Exo-loaded COMA regulate ECM degradation and apoptosis through autophagy. Additionally, this study introduced si-peroxisome proliferator-activated receptor γ (PPARγ) into HP-Exo, whereby the engineered Exo within the hydrogel induced ECM regeneration and suppressed apoptosis via PPARγ-autophagy axis. Injecting HP-Exo@COMA into annulus fibrosus defects in IVDD rat models significantly promoted ​​structural-functional IVD repair​​, demonstrating the synergistic regeneration of both nucleus pulposus tissue and annulus fibrosus architecture. This strategy may provide a therapeutic approach to restore ​​postoperative IVD. STATEMENT OF SIGNIFICANCE: : A collagen methacrylate (COMA) hydrogel loaded with hypoxic preconditioning exosomes (HP-Exo) was developed for intervertebral disc (IVD) repair after discectomy. This hydrogel enabled the sustained release of HP-Exo while providing mechanical support. HP-Exo@COMA promotes coordinated regeneration of the nucleus pulposus and annulus fibrosus by activating the PPARγ-autophagy axis, thereby inducing extracellular matrix regeneration and inhibiting apoptosis. This study presents a novel therapeutic strategy for postoperative IVD repair.