Cartilage Endplate-Targeted Engineered Exosome Releasing and Acid Neutralizing Hydrogel Reverses Intervertebral Disc Degeneration.

Abstract

Cartilage endplate cell (CEPC) and nucleus pulposus cell (NPC) inflammation are critical factors that contribute to intervertebral disc degeneration (IVDD). Recent evidence indicated that iron ion influx, reactive oxygen species (ROS), and the cGAS-STING pathway are involved in CEPC inflammatory degeneration. Moreover, cytokines produced by degenerating CEPCs and lactic acid accumulation within the microenvironment significantly contribute to NPC inflammation. Consequently, simultaneous alleviation of CEPC inflammation and correction of the acidic microenvironment are anticipated to reverse IVDD. Herein, CEPC-targeted engineered exosomes loaded with salvianolic acid A are incorporated into a CaCO₃/chitosan hydrogel, forming a composite gel, CAP-sEXOs@Gel. Notably, CAP-sEXOs@Gel shows long local retention, realizes the slow release of CAP-sEXOs and specific uptake by CEPCs. After uptake by CEPCs, CAP-sEXOs reduce intracellular iron ion and ROS by inhibiting hypoxia-inducible factor-2α (HIF-2α)/TfR1 expression. Iron ion influx and ROS inhibition contribute to the maintenance of normal mitochondrial function and reduced mtDNA leakage, suppresing the cGAS-STING pathway. Additionally, the CaCO₃ component of CAP-sEXOs@Gel neutralizes H⁺, thereby alleviating NPC inflammation. Collectively, this novel composite hydrogel demonstrates the ability to concurrently inhibit CEPC and NPC inflammation, thereby presenting a promising therapeutic approach for IVDD.