Background: The primary strategy to repair peripheral nerve injuries is to bridge the lesions by promoting axon regeneration. Thus, the ability to direct and manipulate neuronal cell axon regeneration has been one of the top priorities in the field of neuroscience. A recent innovative approach for remotely guiding neuronal regeneration is to incorporate magnetic nanoparticles (MNPs) into cells and transfer the resulting MNP-loaded cells into a magnetically sensitive environment to respond to an external magnetic field. To realize this intention, the synthesis and preparation of ideal MNPs is an important challenge to overcome. Results: In this study, we designed and prepared novel fluorescent-magnetic bifunctional Fe 3 O 4 •Rhodamine 6G@ polydopamine superparticles (FMSPs) as neural regeneration therapeutics. With the help of their excellent biocompatibility and ability to interact with neural cells, our in-house fabricated FMSPs can be endocytosed into cells, transported along the axons, and then aggregated in the growth cones. As a result, the mechanical forces generated by FMSPs can promote the growth and elongation of axons and stimulate gene expression associated with neuron growth under external magnetic fields. Conclusions: Our work demonstrates that FMSPs can be used as a novel stimulator to promote noninvasive neural regeneration through cell magnetic actuation.

Peripheral nerve injuries always cause dysfunction but without ideal strategies to assist the treatment and recovery successfully. The primary way to repair the peripheral nerve injuries is to bridge the lesions by promoting axon regeneration. Schwann cells acting as neuroglial cells play a pivotal role during axonal regeneration. The orderly and organized migration of Schwann cells is beneficial for the extracellular matrix connection and Bungner bands formation, which greatly promote the regeneration of axons by offering mechanical support and growth factors. Thus, the use of Schwann cells as therapeutic cells offers us an attractive method for neurorepair therapies, and the ability to direct and manipulate Schwann cell migration and distribution is of great significance in the field of cell therapy in regards to the repair and regeneration of the peripheral nerve. Herein, we design and characterize a type of novel fluorescent−magnetic bifunctional Fe 3 O 4 •Rhodamine 6G (R6G)@polydopamine (PDA) superparticles (SPs) and systematically study the biological behaviors of Fe 3 O 4 •R6G@PDA SP uptake by Schwann cells. The results demonstrate that our tailor-made Fe 3 O 4 •R6G@PDA SPs can be endocytosed by Schwann cells and then highly magnetize Schwann cells by virtue of their excellent biocompatibility. Furthermore, remote-controlling and noninvasive magnetic targeting migration of Schwann cells can be achieved on the basis of the high magnetic responsiveness of Fe 3 O 4 •R6G@PDA SPs. At the end, gene expression profile analysis is performed to explore the mechanism of Schwann cells' magnetic targeting migration. The results indicate that cells can sense external magnetic mechanical forces and transduce into intracellular biochemical signaling, which stimulate gene expression associated with Schwann cell migration.

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Neuroanatomical tracing is considered a crucial technique to assess the axonal regeneration level after injury, but traditional tracers do not meet the needs of in vivo neural tracing in deep tissues. Magnetic resonance (MR) and photoacoustic (PA) imaging have high spatial resolution, great penetration depth, and rich contrast. Fe 3 O 4 nanoparticles may work well as a dual-modal diagnosis probe for neural tracers, with the potential to improve nerve regeneration. The present study combines antegrade neural tracing imaging therapy for the peripheral nervous system. Fe 3 O 4 @COOH nanoparticles are successfully conjugated with biotinylated dextran amine (BDA) to produce antegrade nano-neural tracers, which are encapsulated by microfluidic droplets to control leakage and allow sustained, slow release. They have many notable advantages over traditional tracers, including dual-modal real-time MR/PA imaging in vivo, long-duration release effect, and limitation of uncontrolled leakage. These multifunctional anterograde neural tracers have potential neurotherapeutic function, are reliable and may be used as a new platform for peripheral nerve injury imaging and treatment integration.