ROS-responsive hydrogel loaded with berberine liposome protects against intervertebral disc degeneration by inhibiting mitochondrial fission and apoptosis

Intervertebral disc degeneration (IVDD) is closely associated with mitochondrial dysfunction caused by the excessive accumulation of reactive oxygen species (ROS). Current therapeutic strategies are limited in their ability to precisely intervene in mitochondrial dynamics imbalance. This study develops a ROS-responsive hydrogel crosslinked via dynamic borate ester bonds between boric acid-modified hyaluronic acid and polyvinyl alcohol (PVA), which was further loaded with berberine liposomes (HP-Lipo@BBR), aiming to scavenge excessive ROS, and restore mitochondrial function. The hydrogel exhibited excellent degradability, injectability, self-healing properties, antioxidative effects, and biocompatibility. It triggers intelligent drug release in the high-ROS microenvironment of degenerated discs. The liposomes efficiently encapsulate berberine, facilitating intracellular drug delivery via the endocytosis of nucleus pulposus cells. Mechanistically, berberine scavenges ROS, inhibits abnormal phosphorylation of dynamin-related protein 1 (p-Drp1), and reduces excessive mitochondrial fission, thereby blocking the caspase-3-mediated apoptosis pathway. In a rat disc puncture degeneration model, intradiscal injection of HP-Lipo@BBR effectively maintains intervertebral disc height and the hydration of nucleus pulposus tissue, inhibits mitochondrial fission-apoptosis axis, and improves the regeneration of extracellular matrix, with therapeutic effects significantly superior over free berberine or hydrogel. This study provides a new strategy for minimally invasive treatment of IVDD and other related degenerative diseases.