Sodium oxamate-functionalized microspheres alleviate Intervertebral disc degeneration by inhibiting excessive glycolysis in nucleus pulposus cells.

Abstract

Intervertebral disc degeneration (IVDD) is a leading contributor to low back pain and is characterized by a proinflammatory microenvironment and disruption of extracellular matrix (ECM) metabolic homeostasis. Although aberrant glycolytic reprogramming has been implicated in IVDD pathogenesis, effective therapeutic strategies targeting this metabolic dysregulation remain limited. To address this gap, we developed the injectable gelatin methacrylate (GelMA) microspheres functionalized with sodium oxamate (SO) and co-loaded with transforming growth factor-β3 (TGF-β3) (S-T@GM) to enable the synergistic metabolic and regenerative therapy. Following confirmation of glycolytic abnormalities in human degenerated disc tissues and TNFα-stimulated nucleus pulposus cells (NPCs), we systematically characterized the biocompatibility of S-T@GM microspheres and evaluated their therapeutic efficacy both in vitro and in a rat puncture-induced IVDD model. SO effectively normalized glycolytic flux and attenuated inflammatory responses in NPCs; notably, the combined S-T@GM treatment-unlike either component alone-most efficiently restored ECM homeostasis by enhancing type Ⅱ collagen (COL Ⅱ) synthesis while suppressing the catabolic enzyme ADAMTS5. In vivo, S-T@GM treatment provided superior preservation of disc height, nucleus pulposus hydration, and overall tissue architecture, with immunohistochemical analyses confirming concurrent inflammation suppression and sustained COL Ⅱ retention. Collectively, these findings demonstrate that glycolytic reprogramming via SO synergizes potently with TGF-β3 to mitigate IVDD progression, and that the S-T@GM microsphere platform represents a promising integrative strategy that simultaneously targets metabolic dysfunction and impaired regeneration for effective intervertebral disc repair.