Enhancing the Therapeutic Potential of Nanoparticle-Mediated Immunotherapeutics for Spinal Trauma

Traumatic primary spinal cord injury (SCI) can initiate complex secondary biological processes, including inflammation, which may lead to various neurological diseases. Although acute interventions targeting inflammation show promise, current therapies mainly aim to prevent further chronic damage to the injured spinal cord by focusing on strategies like lesion stabilization and rehabilitation. While these strategies may prolong the lifespan of SCI patients, developing acute therapeutic interventions that specifically target inflammation has the potential to greatly enhance the quality of life for the entire SCI population. This proposal aims to address this gap by utilizing biocompatible Poly (lactide-co-glycolide, 50:50) acid (PLG)-based nanoparticles (NPs), which effectively mitigate secondary inflammatory responses. Our central hypothesis is that intravenously administered NPs will function as a minimally invasive therapeutic platform, aimed at reprogramming innate immune cells during the acute phase of SCI. This reprogramming is expected to target pro-inflammatory immune subsets in the bloodstream before they migrate to the injury site, inducing changes in their phenotype and thereby creating a sustained permissive microenvironment. Ultimately, this modulated microenvironment has the potential to improve functional outcomes. Importantly, these effects are solely medicated by their unique physicochemical properties, without the involvement of active biologics that might lead to undesirable off-target effects. The primary goal of this study is to enhance the therapeutic efficacy of NPs for diseases associated with inflammatory responses. To achieve this, we will focus on investigating two specific aims. Studies under Aim 1 will determine the most effective therapeutic ranges and treatment durations of NPs. Three different NP doses (i.e., 25, 50, or 75 mg/kg) will be administered daily for three different durations (i.e., 1, 3, or 7 days), then the interaction between NPs and innate immune cells will be investigated. In Aim 2, we will identify the optimal therapeutic time window of NP administrations to facilitate functional recovery building upon the established dose and treatment duration from Aim 1. SCI animals will receive NPs at three different time points (i.e., 0.5, 24, or 48 hours post-initial spinal trauma). The successful completion of our studies will provide valuable therapeutic data for NPs, contributing to the development of more effective minimally invasive immunotherapeutic strategies for neural trauma. As we optimize our NP-driven immunotherapy approach, our focus will transition to conducting a comprehensive large-scale study. This study will aim to identify the key physicochemical design parameters of NPs, a vital step towards tailoring personalized NP-medicated immunotherapy for potential clinical application in our future study.