Injectable mRNA-engineered short fibers deliver temporally coupled mechano-genetic signals to reprogram Schwann cell cytoskeleton for nerve repair

Defective Schwann cell (SC) repair programs mediated by cytoskeletal remodeling severely limit functional recovery following peripheral nerve injury (PNI). Here, we report an in situ mRNA therapy enabled by an injectable, mechanically/genetically time-sequenced short-fiber platform (A-CJM-LNP@SF) that reprograms SC cytoskeletal dynamics to accelerate repair. Polydopamine-coated, mechanically sheared electrospun short fibers adsorb c-Jun mRNA-loaded lipid nanoparticles (LNPs), enhancing local retention and providing sustained mechanical cues. Early after injury, efficient transfection elicits a transient intracellular c-Jun pulse that activates Rac1/Cdc42-associated cytoskeletal programs, promoting myelin debris clearance and induction of the repair phenotype. Subsequently, the relatively slow-acting mechanical stimulation, once released from c-Jun inhibition, sustains RhoA signaling, driving SC alignment and remyelination. In vitro and in vivo data confirm coordinated SC phenotypic transitions and remyelination, with >4 folds increases in day-3 SC abundance and day-28 conduction velocity over untreated crush, substantially improving sensory and motor functional recovery. Overall, coupling transient mRNA delivery with sustained mechanical stimulation offers a powerful strategy for PNI regeneration.