Developing immunotherapeutic nanoparticles for spinal cord injury

创伤性脊髓损伤（SCI）导致原发性损伤，随后是继发性损伤，包括炎症，其产生抑制性环境。由于额外的组织损伤和抑制性环境，再生受到限制，导致各种神经功能缺损。该提案的目标是开发一种非侵入性的急性干预措施，目的是调节炎症反应，以重新编程SCI后的抑制环境。特别是，SCI人口统计学在男性和女性之间朝着更平等的平衡转变，这表明需要改进治疗方法，因为性别之间生理因素的差异在SCI后的药物治疗和功能恢复中起着重要作用。在这项研究中，基于聚（丙交酯-共-乙交酯）（PLG）的多纳米颗粒（NP）制剂将被设计为具有各种物理化学因素，以识别NP的性别特异性关键功能，以重新编程炎症，从而分别促进SCI后女性和男性的功能恢复。具体目标1将研究SCI后NP诱导的先天细胞调节，以确定NP的性别特异性关键特性。NP的独特物理化学性质将不同地限制SCI后的炎症。具体目标2将评估脊髓中NPs介导的长期动态反应及其对SCI后两性解剖和功能恢复的影响。静脉内（IV）施用的NP将结合免疫群体的促炎亚群并将其运输引导至脾脏。受损组织内的NP阳性先天细胞将导致持续的反应，促进改善SCI后恢复的环境。成功完成所提出的目标将提供有效的性别特异性NP设计，以最大限度地提高SCI后的功能恢复。此外，NP由FDA批准的材料制成，使得NP能够在分诊中或现场施用于诊断为SCI的患者，而无需直接干预脊髓。这项研究将为整个SCI人群提供一种潜在的实用治疗方法。

Traumatic spinal cord injury (SCI) leads to primary injury, followed by secondary injuries including inflammation which create an inhibitory environment. Regeneration is limited due to additional tissue damages and an inhibitory environment, leading to various neurological deficits. The goal of this proposal is to develop a non-invasive acute intervention with the goal of modulating inflammatory responses to reprogram an inhibitory environment after SCI. Particularly, the SCI demographic shifts toward a more equal balance among males and females, indicating that improved therapeutics are needed since the difference in physiological factors between sexes play important roles in pharmacological treatments and functional recovery after SCI. In this study, Poly(lactide-co-glycolide) (PLG)-based multiple nanoparticle (NP) formulations will be designed with various physicochemical factors to identity sex-specific key functionality of NPs to reprogram inflammation, thereby facilitating functional recovery in females and males respectively after SCI. Specific aim 1 will investigate NP-induced innate cells modulation following SCI to identify sex-specific key properties of NPs. The distinct physicochemical properties of NPs will differently limit inflammation after SCI. Specific aim 2 will assess NPs-mediated long-term dynamic responses in the spinal cord and their effects on anatomical and functional recovery in both sexes after SCI. Intravenously (IV) administered NPs will bind to pro-inflammatory subsets of immune populations and direct their trafficking to the spleen. NP-positive innate cells within the injured tissues will lead to a sustained response, facilitating an environment that improves recovery after SCI. Successful completion of proposed aims will provide efficient sex-specific NP designs to maximize functional recovery after SCI. In addition, NPs are made of FDA-approved material that enables NPs to be administered in triage or on site to patients diagnosed with SCI without direct intervention into the spinal cord. This study will provide a potentially practical therapy for the entire SCI population.