Harnessing Engineered Drug-Free Polymeric Nanoformulations To Reprogram Innate Immune Cells For Spinal Trauma

Project Summary/Abstract The endogenous tissue regeneration after traumatic spinal cord injury (SCI) is limited due to an inhibitory environment by secondary biological events including inflammatory responses. These events result in neural cell death and demyelination leading to various inflammation-mediated disorders. The long-term goal of this study is to develop effective acute intervention strategies that limit secondary injuries, thereby creating a permissive environment that supports regeneration. To achieve this goal, polymer based-nanoparticle (NP) formulations will be employed to reprogram the circulating innate cells in the blood after trauma. The scientific premise of the proposed research is based on preliminary data demonstrating that intravenously administered NPs target the pro-inflammatory sub-set of immune cells prior to extravasation to the injury and reprogram their trafficking patterns and phenotypes that limit inflammation and additional tissue damage, thereby inducing enhanced regeneration. Particularly, the immunomodulation is mediated by the physicochemical properties of NPs, indicating that NPs functions can be engineered differently to influence immune trafficking and phenotypes. The proposed engineered-NP formulations differentially reprogram innate cells, specifically immunomodulatory effects of NPs are sex-dependent and, importantly, these effects are solely mediated by distinctive physicochemical properties of NPs without the active biologics that can cause unfavorable off-target effects. In this proposal, key physicochemical parameters of NP formulations will be identified for effective immunomodulation in males and females respectively since the differences in physiological factors between sexes play a critical role in inflammation after spinal trauma. Aim 1 will focus on interactions between different NP formulations and innate cells in circulation to identify more effective NP design factors that limit inflammation in both sexes. Distinct physicochemical properties of NPs will differently affect innate cells trafficking and phenotype, which will be sex-dependent and subsequently, reprogram an inhibitory environment. NP-induced differential cellular internalization, phenotype, activation, pharmacokinetic profiles as well as biodistribution of NPs will be investigated. Aim 2 will investigate the long-term impacts of NPs on anatomical and functional regeneration after SCI with a more focused set of NP formulations based on Aim 1. Initially, NP-associated immune cells will be investigated, then the extent of axonal regrowth and remyelination, synaptogenesis, and functional recovery in the chronic phase of SCI will be assessed. Collectively, the proposed studies will have the potential to be a transformational therapy by identifying the relationship between physicochemical parameters and immune modulation for effective NP formulations to support regeneration. Notably, NPs are made of FDA- approved polymeric biomaterial enabling them to be readily stored for immediate administration non-invasively as a means to modulate the innate immune system for functional enhancement.