A Novel Superparamagnetic Multifunctional Nerve Scaffold: A Remote Actuation Strategy to Boost In Situ Extracellular Vesicles Production for Enhanced Peripheral Nerve Repair

Abstract Extracellular vesicles (EVs) have inherent advantages over cell‐based therapies in regenerative medicine because of their cargos of abundant bioactive cues. Several strategies are proposed to tune EVs production in vitro. However, it remains a challenge for manipulation of EVs production in vivo, which poses significant difficulties for EVs‐based therapies that aim to promote tissue regeneration, particularly for long‐term treatment of diseases like peripheral neuropathy. Herein, a superparamagnetic nanocomposite scaffold capable of controlling EVs production on‐demand is constructed by incorporating polyethyleneglycol/polyethyleneimine modified superparamagnetic nanoparticles into a polyacrylamide/hyaluronic acid double‐network hydrogel (Mag‐gel). The Mag‐gel is highly sensitive to a rotating magnetic field (RMF), and can act as mechano‐stimulative platform to exert micro/nanoscale forces on encapsulated Schwann cells (SCs), an essential glial cell in supporting nerve regeneration. By switching the ON/OFF state of the RMF, the Mag‐gel can scale up local production of SCs‐derived EVs (SCs‐EVs) both in vitro and in vivo. Further transcriptome sequencing indicates an enrichment of transcripts favorable in axon growth, angiogenesis, and inflammatory regulation of SCs‐EVs in the Mag‐gel with RMF, which ultimately results in optimized nerve repair in vivo. Overall, this research provides a noninvasive and remotely time‐scheduled method for fine‐tuning EVs‐based therapies to accelerate tissue regeneration, including that of peripheral nerves.