A Dual-Strategy Hydrogel Targeting Glycolytic Reprogramming and Inflammation to Inhibit Ferroptosis and Promote Intervertebral Disc Repair.

Intervertebral disc degeneration (IVDD) is a major cause of lower back pain, and its progression is largely driven by metabolic changes, particularly enhanced glycolysis. Lactate, a by-product of glycolysis, induces ferroptosis in nucleus pulposus cells (NPCs). Inflammation further enhances glycolysis in NP cells and upregulates lactate dehydrogenase A (LDHA), leading to increased lactate accumulation and the formation of a vicious cycle that accelerates IVDD progression. In this study, an innovative dual-strategy hydrogel system was designed to address these limitations. Phenylboronic acid (PBA) -functionalized G5 PAMAM (G5-PBA) was used to encapsulate LDHA siRNA (siLDHA), forming self-assembled nanoparticles (GPS). Subsequently, GPS was modified with epigallocatechin (EGC) to form stable GPS-EGC nanoparticles through borate ester bonds. The nanoparticles were then incorporated into a reactive oxygen species- and pH-responsive hydrogel, enabling controlled and sustained drug release. By combining metabolic reprogramming with anti-inflammatory strategies, the designed system not only reduced IL-1β-induced inflammation and lactate production but also alleviated ferroptosis in NPCs and promoted tissue repair in IVDD models. This approach offers a promising therapeutic strategy for IVDD and highlights the potential of material innovation in modulating both metabolic and inflammatory pathways.