Abstract

Intervertebral disc degeneration (IVDD) is the major pathological cause of low back pain and global disability. Its chronic and persistent inflammatory microenvironment, resembling a flowing flood to erode the ecosystems relentlessly, disrupts the intervertebral disc homeostasis. In the present study, we first verified that Notch signaling is negatively correlated with inflammation in IVDD samples. Meanwhile, we identified a natural flavonoid hesperetin (Hes) as a potential agonist of Notch1 by molecular docking predicting. Herein, we developed an EV-inspired bioactive reservoir system, in which the natural extracts hes was encapsulated into liposomes (Hes@lipo) and embedded within a gelatin methacryloyl (GM) hydrogel (GM/Hes@lipo)to achieve sustained release. By mimicking the extracellular matrix (ECM)-like microenvironment of the intervertebral disc (IVD), GM/Hes@lipo provided physiological environment for nucleus pulposus cells (NPCs) adhesion and growth maintenance. Furthermore, by activating Notch signaling, GM/Hes@lipo effectively restored the dynamic balance between pro- and anti-inflammatory cytokines and maintained ECM metabolic homeostasis, attenuating NOD-like receptor signaling, thereby inhibiting NPC pyroptosis. Based on these aspects, GM/Hes@lipo relieved the IVDD process, maintained annulus fibrosus integrity, and effectively alleviated discogenic pain after the platform was administrated into the intervertebral disc of the rats. Collectively, as an anti-inflammatory “flood-control” system, the Notch signaling-targeted biomimetic hydrogel presents a biomimetic–natural compound combinatorial strategy offering promising therapy for mitigating IVDD progression.