The protection of chitosan-coated triptolide-magnesium nanoparticles against intervertebral disc degeneration via MAPK signaling and mitophagy.

OBJECTIVE: This study aimed to develop chitosan-based nanoparticles (ChNPs) for Triptolide (TPL) delivery to mitigate intervertebral disc degeneration (IDD). METHODS: TPL-magnesium (Mg) ChNPs were prepared by mixing TPL, magnesium sulfate, and chitosan under controlled stirring, followed by nanoparticle characterization. An in vitro IDD model was established by stimulating nucleus pulposus cells (NPCs) with IL-1β. The therapeutic effect and biosafety of TPL-Mg ChNPs was assessed using cell counting kit-8. In an in vivo IDD rat model, pathology of intervertebral discs was evaluated via micro-computed tomography and histological staining. Western blotting, immunofluorescence, and immunohistochemistry were used to assess MAPK signaling, mitophagy activity, and extracellular matrix (ECM) programs. RESULTS: TPL inhibited the proliferation of IL-1β-induced NPCs. TPL was complexed with Mg2+, and further coated with chitosan via electrostatic adsorption to obtain TPL-Mg ChNPs. TPL-Mg ChNPs exhibited physical stability and biosafety, and could control drug release. TPL-Mg ChNPs were internalized by damaged NPCs within 4 hours and inhibited reactive oxygen species release. In vitro, TPL-Mg ChNPs protected NPCs and maintained ECM metabolic balance. In vivo, TPL-Mg ChNPs significantly improved IDD pathology in rats by inhibiting MAPK signaling and activating mitophagy. CONCLUSION: TPL-Mg ChNPs ameliorate IDD progression by inhibiting the MAPK pathway and activating mitophagy.