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

ABSTRACT 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.