Quercetin nanoformulation-embedded hydrogel inhibits osteopontin mediated ferroptosis for intervertebral disc degeneration alleviation.

Reactive oxygen species (ROS) play a pivotal role in multiple events during the progression of intervertebral disc degeneration (IDD). Hence, the precision treatment targets associated with ROS should be further explored to promote developing effective therapeutic strategies. In this study, by analyzing specimens from patients and RNA sequencing of ROS-induced human primary nucleus pulposus cells (NPCs), osteopontin (OPN) and ferroptosis were identified as critical molecular entities and cellular pathways implicated in ROS-mediated IDD. Subsequent animal models and cellular assays determined that ROS induced upregulation of OPN, which in turn triggered ferroptosis in NPCs and intervertebral discs, consequently leading to IDD. Building upon these findings, a comprehensive screening of molecular drug database revealed that quercetin, an antioxidant molecule compound, possesses the capacity to couple OPN, thereby mitigating OPN-induced ferroptosis and IDD. In addition, the compound of quercetin for targeting OPN was encapsulated in phenylboric acid modified dendrimer (G3-PBA) nanoparticles to improve its solubility, and then embedded in a ROS-degradable and injectable hydrogel, thereby achieving on-demand release of quercetin with the progression of IDD. Collectively, this study not only identified a novel therapeutic target, but also engineered an effective therapeutic strategy intended for the autonomous management of IDD.