Polydopamine‐Mediated Thermotherapy Hydrogel for Disc Degeneration Inhibition via Modulating Inflammation and Extracellular Matrix Metabolism

ABSTRACT Intervertebral disc degeneration (IVDD), frequently accompanied by low back pain, is a global public health challenge. Current therapeutic approaches are unable to halt IVDD progression due to their limited efficacy in promoting extracellular matrix (ECM) remodeling and suppressing inflammatory cascades. To address these issues, we develop an injectable hydrogel‐based thermotherapy platform incorporating mesoporous polydopamine (mPDA) nanoparticles (NPs), termed mPDA@Gel. The introduction of mPDA NPs confers dual therapeutic benefits—efficient photothermal conversion and potent reactive oxygen species scavenging, while the prolonged retention of hydrogel matrix within the intervertebral disc (IVD) enables repeated thermotherapy interventions and exerts sustained anti‐inflammatory effects following a single injection of mPDA@Gel. In vitro studies demonstrate that multiple mild thermotherapies combined with mPDA NP administration effectively restore ECM metabolic homeostasis in lipopolysaccharide‐stimulated nucleus pulposus cells (NPCs) by modulating inflammatory signaling pathways. In vivo evaluation using a rat model of IVDD reveals that a single IVD administration of mPDA@Gel followed by multiple mild thermotherapy cycles significantly reduces disc height loss, minimizes ECM degradation, alleviates inflammatory responses, inhibits NPC apoptosis, relieves non‐specific pain, and preserves biomechanical functions. These findings suggest that the proposed system offers a promising minimally invasive therapeutic strategy for the management of degenerative musculoskeletal diseases.