Background <p>The remarkable intrinsic regenerative capacity of peripheral nerves following injury is largely attributed to the phenotypic plasticity of Schwann cells (SCs) and their ability to transition into a repair-supportive state (rSCs). Transcriptional reprogramming of SCs into this reparative phenotype is pivotal for facilitating successful nerve regeneration. While traditionally considered a biochemically regulated process, recent advances in mechanobiology have underscored the crucial role of mechanical cues in modulating SC behavior and gene expression. In this study, we sought to develop a magnetically actuated mechanical stimulation platform based on biotargeted magnetic nanoparticles and a custom-engineered gradient magnetic field, enabling the engineering control of SC reprogramming</p> Results <p>We designed and synthesized fluorescent superparamagnetic iron oxide superparticles (f-SPIONs) with specific biotargeting affinity for the actin cytoskeleton, thereby enhancing the spatial precision of nanomagnetic force delivery. In parallel, we engineered a gradient magnetic field generator based on electromagnetic principles to achieve high temporal resolution in magnetic stimulation. By combining f-SPIONs with the external magnetic field, we developed a magnetomechanical stimulation platform capable of remotely delivering noninvasive, high-spatiotemporal-resolution force to SCs and peripheral nerve tissues. Upon magnetic stimulation, SCs exhibited robust reprogramming toward a reparative phenotype, effectively enhancing sciatic nerve regeneration in a rat model. The study of the mechanotransduction mechanism of this phenomenon revealed that f-SPION-mediated magnetic stimulation activated actin cytoskeletal dynamics, gated the opening of mechanosensitive ion channel Piezo1 and triggered calcium influx, ultimately inducing rSC reprogramming</p> Conclusions <p>Schwann cells are highly sensitive to external mechanical environments and are capable of transducing mechanical cues into intracellular biochemical signals, thereby modulating their functional state in response. The “magnetomechanical neuromodulation” strategy, developed through the integration of magnetic nanomaterials and externally applied magnetic fields, represents a promising approach that offers innovative mechanotherapeutic tools and perspectives for biomedical research and the treatment of peripheral nerve injuries</p> Graphical abstract <p></p>