Smart biophysical cue-based strategies and materials for intervertebral disc degeneration therapy

Low back pain (LBP) is the leading cause of non-fatal disability globally, significantly affecting quality of life and imposing an immense socioeconomic burden. Intervertebral disc degeneration (IVDD) is a major cause of LBP. Although advances in biomaterials and drug delivery have provided new therapeutic options, their efficacy remains limited by invasive delivery approaches and the spatiotemporal dynamic changes in the microenvironment during treatment. In recent years, smart biophysical cue-based strategies—represented by electrical, magnetic, photo, ultrasonic, and mechanical cues—have offered breakthrough noninvasive or minimally invasive approaches for IVDD intervention. Such cues can act directly or indirectly on disc tissues, modulating oxidative stress signaling pathways, optimizing the inflammatory microenvironment, and influencing cellular behavior and extracellular matrix metabolism, thereby delaying or even reversing the degenerative process. These modalities possess highly controllable and precise regulatory potential for tissue repair and can synergize with intelligent biomaterials, drug delivery systems, and other therapeutic strategies to achieve multi-dimensional and multi-targeted regulation. Current research in this field has largely concentrated on isolated biophysical cues or individual material systems, resulting in fragmented advances and a lack of systematic cross-comparison, which limits their translational relevance for precise clinical intervention. This review goes beyond single-cue perspectives to provide a comprehensive and comparative integration of multiple biophysical cue-based strategies and materials within the IVDD field, systematically elucidating their mechanisms of action and developmental trajectories. Moreover, from an interdisciplinary perspective, this review provides new theoretical foundations and directions for precision therapy in IVDD. • A comprehensive overview of biophysical cue-based strategies for IVDD therapy. • Biophysical cues enable noninvasive or minimally invasive IVDD therapeutic approaches. • Biophysical cues synergize with smart materials to enable precise and durable tissue repair. • Convergence of medicine and engineering fosters innovative disc regeneration strategies. • Biophysical cue-based therapies offer scalable, patient-friendly pathways toward clinical translation.