Injectable hydrogel encapsulated with VEGF-mimetic peptide-loaded nanoliposomes promotes peripheral nerve repair in vivo

Repair of peripheral nerve crush injury remains a major clinical challenge. Currently, oral or intravenous neurotrophic drugs are the main treatment for peripheral nerve crush injury; however, this repair process is slow, and the final effect may be uncertain. The current study aimed at developing an injectable hydrogel with vascular endothelial growth factor (VEGF)-mimetic peptide (QK)-encapsulated nanoliposomes (QK-NLs@Gel) for sustainable drug release that creates an appropriate microenvironment for nerve regeneration. The QK-encapsulated nanoliposomes (QK-NLs) could facilitate the proliferation, migration, and tube formation capacities of human umbilical vein endothelial cells through the VEGF signaling pathway. The QK-NLs@Gel hydrogel encapsulated with QK-NLs showed enhanced physical properties and appropriate biocompatibility in vitro. Thereafter, the QK-NLs@Gel hydrogel was directly injected into the site of peripheral nerve crush injury in a rat model, where it enhanced revascularization and promoted the M2-polarization of the macrophages, thus providing an optimized microenvironment for nerve regeneration. At four weeks post-surgery, the QK-NLs@Gel injected rats exhibited enhanced axon regeneration, remyelination, and better functional recovery in comparison with other groups in vivo. Overall, these findings demonstrate that the composite hydrogel could promote a multicellular pro-regenerative microenvironment at the peripheral nerve injury site, thus revealing great potential for peripheral nerve restoration. STATEMENT OF SIGNIFICANCE: Peripheral nerve injury (PNI) is a leading public health issue, and how to delivery beneficial drugs to injured sites efficiently is still a big challenge. In the current study, an injectable hydrogel with VEGF-mimetic peptide (QK)-encapsulated nanoliposomes (QK-NLs@Gel) was first developed and used to repair a rat crush injury model. Our results showed that QK-NLs promoted the proliferation, migration, and angiogenesis of HUVEC via VEGF signaling pathway in vitro. Furthermore, when injected to the crushed sites in vivo, the QK-NLs@Gel hydrogel could accelerate nerve repair through enhanced revascularization and M2-polarization of macrophages. These results collectively demonstrate that injection of QK-NLs@Gel hydrogel could create an appropriate microenvironment for peripheral nerve regeneration. This strategy is effective, economical, and convenient for clinical applications.