Pathological microenvironment-responsive nano-glycospheres restore disc homeostasis by combinatorial metabolic and genetic regulation

Intervertebral disc degeneration (IVDD) is fundamentally driven by a self-perpetuating pathological loop involving metabolic derangement, oxidative stress, and enzymatic hyper-activity. Conventional mono-therapies often fall short of reversing this complex microenvironmental collapse. Here, we developed a smart nano-glycosphere (siMMP13/2-DG NPs) designed for dual-track intervention to restore disc homeostasis. This responsive platform utilized a 2-deoxy-D-glucose (2-DG) shell crosslinked via reactive oxygen-sensitive phenylboronic acid moieties, enabling the simultaneous suppression of pathological glycolysis and the neutralization of oxidative stress. Concomitantly, the precise delivery of siMMP13 effectively silenced major catabolic enzymes, thereby arresting extracellular matrix degradation. Our findings demonstrated that this combinatorial approach effectively interrupted the lactate-driven inflammatory cascade, shifting the microenvironment from a hostile catabolic state toward a pro-regenerative metabolic balance. In the lumbar disc degeneration model, the siMMP13/2-DG NPs significantly preserved structural integrity and alleviated discogenic pain by dampening neuro-inflammatory signaling. By integrating metabolic reprogramming with targeted gene silencing, this study establishes a versatile therapeutic paradigm for the precision management of IVDD and offers broader insights into the treatment of other microenvironment-mediated musculoskeletal disorders. Construction of siMMP13/2-DG NPs with 2-DG as a potential therapeutic agent together with siMMP13, alleviation of IVDD by balancing microenvironmental homeostasis