Nanodrug-loaded microneedles promote scar-reduced repair after spinal cord injury by re-establishing microglial homeostasis

Abstract

The persistent activation of microglia is a key factor contributing to neuronal damage and inhibiting the repair of spinal cord injury (SCI). Re-establishing local microglial homeostasis during the early stages of injury presents a novel approach for scar-reduced repair after SCI. Nitroxoline (Nit) can reinstate microglial homeostasis after their activation in vitro. However, the poor water solubility and low blood-spinal cord barrier permeability limit the potential application of Nit in SCI. Here, a dual drug-delivering system (Nit-MNs) composed of self-assembled nano-micelles and gelatin methacryloyl microneedles was further designed. The nano-micelles resolved the solubility issues of Nit while facilitating sustained release. The Nit-MNs enabled continuous drug delivery into the intrathecal space through the micro-perforations created in the dura mater. In the rat spinal cord contusion model, the implantation of Nit-MNs reduced scar formation, promoted neural regeneration, and subsequently restored neurological function. Further studies demonstrated that Nit-MNs promoted the re-establishment of microglial homeostasis, probably through inhibiting the expression of cathepsin B. Therefore, our functional Nit delivery system provides a promising drug-based delivery strategy for SCI treatment.

Statement of significance

Small molecule drugs have demonstrated therapeutic effects by targeting various pathological processes of SCI, but the efficacy and precise delivery often limit their broader application. In this study, we identified a small molecule drug (Nit) as a potential candidate for promoting SCI repair by facilitating the re-establishment of microglial homeostasis. Additionally, we developed a dual drug-delivering system comprising self-assembled nano-micelles and gelatin methacryloyl microneedles. This system achieved transdural delivery and dual sustained release of Nit at the precise injury site, effectively promoting the scar-reduced repair after SCI. Our research provides insights for the development of novel delivery systems that match the therapeutic characteristics of small molecule drugs for SCI.