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

作者：Jian Zhang, Yang Li, Rui Ding, Chongzhi Pan, Jiajun Xie, Guanfeng Huang, Xiao‐Long Chen, Xiaokun Zhao, Xinxin Miao, Xigao Cheng · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03718-y · 被引用次数：9 · 研究领域：Spine and Intervertebral Disc Pathology、Tendon Structure and Treatment、Spondyloarthritis Studies and Treatments

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 ...