Anti-Swelling Hydrogel Combined With Nucleus Pulposus Cell Exosomes and Senolytic Drugs Efficiently Repair Intervertebral Disc Degeneration.

Abstract

Intervertebral disc degeneration (IVDD) is a multifactorial pathology primarily driven by the senescence of nucleus pulposus cells (NPC), inflammatory microenvironment of extracellular matrix (ECM), and the resultant decline in NPCs viability. Conventional treatment strategies often fail to address these two interconnected factors simultaneously. To overcome this limitation, a bifunctional anti-swelling hydrogel system encapsulating anti-senescence drugs quercetin (Q) and dasatinib (D), as well as nucleus pulposus-derived exosomes (NP-Exo) is developed. This system is designed to clear senescent NPCs, regulate the inflammatory disc microenvironment, and enhance NPC activity, thereby significantly improving treatment efficacy. Mechanistically, this strategy helps preserve mitochondrial function, maintain mitochondrial membrane potential, and reduce excessive reactive oxygen species production, which collectively contribute to delaying cellular senescence and restoring disc homeostasis. Additionally, the anti-swelling property of the hydrogel can alleviate structural displacement caused by swelling, further optimizing the stability and efficacy of the treatment. The biological efficacy of this system is validated in both rat and goat models. The experimental results demonstrated that this drug delivery system can effectively restore the integrity of the ECM, ultimately promoting the repair of IVDD. These findings highlight the platform's potential for IVDD treatment, offering a novel therapeutic strategy for IVDD repair.