Nanocarriers as vectors to up- or downregulate signal transduction pathways in peripheral nerve regeneration

Peripheral nerve injury is a relatively common event that is ineffective when the nerve injury is severe and the two nerve stumps are separated, requiring a graft to bridge them. Artificial conduits are frequently employed as an advantageous alternative approach to autografts. Macrophages colonize these scaffolds, releasing vascular endothelial growth factor (VEGF-A) -stimulating angiogenesis-, while nerve fibroblasts release soluble neuregulin 1 (NRG1) -stimulating Schwann cell dedifferentiation and migration- and VEGF-A, aiding in nerve regeneration. Furthermore, nerve fibroblasts mainly express the NRG1 α isoform, while Schwann cells primarily express the β isoform, but the different roles of these isoforms have not yet been fully elucidated.

Regeneration within conduits is inefficient when the injury repair is delayed, possibly because cells in the distal portion of the injured nerve lose the ability to release adequate amounts of the factors necessary for nerve regeneration. Nanoscience plays a crucial role in addressing these limitations, offering therapeutic advancements to overcome these deficiencies. For this reason, in this work we analysed the factors released within the conduit after immediate repair and delayed nerve repair and we proposed to enrich nerve conduits with polymeric nanocapsules (PLGA, among others) containing VEGF-A and recombinant soluble NRG1 to obtain a controlled release of these factors when their expression is not sufficient to promote nerve repair. Moreover, it is necessary to find out what the exact roles of NRG1 α and β are. Thus, silencing each of these isoforms is a strategy that would provide knowledge about essential signalling pathways in nerve regeneration. Hence, small interfering RNAs (siRNAs) bioconjugated to polyethylene glycol-coated gold nanoparticles (AuNPs) were developed and will be used to this aim.