A Magneto‐Mechanically Activated Nerve Guidance Conduit Promotes Peripheral Nerve Regeneration via TIMP1‐Mediated Membrane Tension Transfer

Abstract

ABSTRACT Despite architectural advances, current nerve guidance conduits inadequately replicate the mechanoactive microenvironment required for functional neural regeneration. While membrane tension is increasingly recognized as an important biomechanical regulator of axonal extension and glial behavior, its therapeutic exploitation in peripheral nerve repair remains limited. Whether and how membrane tension‐related cues are relayed from support cells to neurons also remains unclear. Here, we developed a magneto‐mechanical augmentation strategy by functionalizing mesenchymal stem cells with superparamagnetic Fe 3 O 4 @polydopamine nanoparticles (FP@MSCs) and incorporating these cells into an aligned PCL/GelMA conduit. Under static magnetic stimulation, FP@MSCs showed increased membrane tension, cytoskeletal remodeling, and accelerated differentiation toward a Schwann cell‐like phenotype. Mechanistically, transcriptomic profiling and protein‐protein interaction mapping pointed to TIMP1 as a candidate paracrine mediator, which subsequently activated the ITGB1/CD63–FAK axis in recipient NE‐4C cells. Further analyses, including atomic force microscopy and osmotic perturbation, indicated that elevated membrane tension drove TIMP1 secretion, which subsequently amplified membrane tension in NE‐4C and promoted neuronal differentiation. In a rat 15 mm sciatic nerve gap model, the magneto‐mechanically activated conduit promoted motor, sensory and histological recovery. Together, these findings support a TIMP1‐dependent intercellular mechanotransductive pathway and suggest a magneto‐mechanical strategy for enhancing the regenerative performance of nerve guidance conduits.