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

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.