ROS-degradable hydrogel delivering LOXL2-LNPs rescues disc degeneration by synchronously suppressing cellular senescence and oxidative damage.

BACKGROUND

Intervertebral disc degeneration (IDD) is a chronic degenerative disorder marked by nucleus pulposus cells (NPCs) senescence and extracellular matrix (ECM) degradation, which is a key pathological factor leading to low back pain. Current clinical treatments are mainly limited to symptomatic relief without effectively reversing the degenerative process.

RESULTS

We revealed that lysyl oxidase-like protein 2 (LOXL2) is involved in the molecular mechanism of NPCs senescence through the regulation of the Notch signaling pathway, and developed a novel therapeutic strategy. We propose an injectable, degradable and ROS-responsive hydrogel delivery system (LNP-LOXL2@Gel), which mimics the biomechanical properties of natural intervertebral disc tissues and can be used as a sustained-release vehicle for LNP-LOXL2. Its ROS scavenging ability complements the intracellular anti-aging effect of LOXL2, blocking the cascade of "oxidative stress-cellular senescence-ECM degradation". In the rat IDD model, LNP-LOXL2@Gel not only reduced nucleus pulposus senescence, but also inhibited ECM catabolism by decreasing the expression of ROS in the microenvironment, thus partially restoring the physiological function of the intervertebral disc.

CONCLUSIONS

LOXL2 expression is down-regulated in degenerated discs, and its overexpression inhibits the Notch pathway and delays NPCs senescence. The LNP-LOXL2@Gel hydrogel system, which can effectively alleviate IDD by synergistically integrating the antiaging effect of LOXL2 and the ROS scavenging ability of PVA-tsPBA, provides a new targeting therapeutic strategy for the clinical treatment of IDD.