Targeting the ROS-senescence-fibrosis axis: A dual-pronged strategy against intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is a prevalent spinal disorder with unclear etiology and limited treatment options. Through integrative analysis of single-cell transcriptomics and validation in clinical specimens, we identified a self-sustaining “ROS–senescence–fibrosis” vicious axis that critically promotes IDD progression, accompanied by significant upregulation of PDE4B in degenerative nucleus pulposus cells (NPCs). To disrupt this pathogenic circuit, we repurposed the clinical PDE4B inhibitor Nerandomilast (Nd) and constructed a biomimetic dual-pronged system for its precise delivery. This system comprises NPC membrane-derived nanovesicles for targeted intracellular Nd delivery to break the ROS–senescence–fibrosis axis, combined with a type II collagen (Col2)-loaded hyaluronic acid hydrogel for synergistic remodeling of the degenerative microenvironment. Both in vitro and in vivo experiments demonstrated excellent biocompatibility and significant efficacy in delaying IDD progression. This research establishes a mechanism-target-material strategy by integrating pathological insights with advanced nanocarrier design, which not only offers a promising therapeutic paradigm for IDD but also provides a conceptual framework for treating other fibrosis-driven degenerative diseases.