Nanoparticle-mediated reprogramming of circulating monocytes and neutrophils to decrease inflammation-mediated damage after trauma

总结：损伤后的组织再生可能由于强烈的炎症反应的发展而受到限制。 反应，可导致大量的细胞死亡和不适当的调节当地的环境， 变得缺乏刺激因子而具有过量的抑制因子。我们的长期目标是发展 纳米颗粒，在创伤后重新编程血液中单核细胞和中性粒细胞的表型， 改变的运输和抗炎表型，减少损害的程度，并可能支持 环境，以增强再生。提出的研究的前提是基于我们的 初步数据表明以微创方式递送纳米颗粒的能力， 炎症单核细胞和嗜中性粒细胞在血液中重新编程其功能，这导致大量的 脊髓模型中的功能恢复。颗粒可以通过多种机制提高采收率， 包括减少损伤处的免疫细胞积聚，调节 已知其协调炎症反应，或直接诱导抗炎或促再生反应， 受伤的环境。以下目的采用与单核细胞具有差异结合的纳米颗粒， 中性粒细胞，这影响其表型，如运输和细胞因子的产生。重要的是 重编程仅由纳米颗粒的物理化学性质介导（例如，尺寸，费用， 组合物），并且不涉及活性药物成分（API），其已经停产 由于风险收益比，许多应用程序。本文的重点是确定 颗粒增强功能恢复，这也可以确定更有效的设计参数。 目标1将研究纳米颗粒与循环中先天免疫细胞的结合，以及它们随后的 运输和炎症反应中的表型。SCI后的纳米颗粒注射导致 实质性的恢复增益我们的目标是确定颗粒促进恢复的机制。 诱导单核细胞和中性粒细胞差异结合、表型极化和运输的颗粒 将被调查。目的2将研究重编程免疫细胞对微环境的影响 在脾脏和脊髓中最初在整个恢复过程中研究基质细胞和免疫细胞， 我们随后研究轴突生长、髓鞘形成和功能恢复的程度。总的来说，这些 研究将确定纳米颗粒特性、免疫调节和免疫调节能力之间的关系。 环境以减少损害并促进功能恢复。我们认为， 基于其物理化学性质的重编程有可能成为一种转化疗法， 通过提供一种容易获得的、非侵入性的方法来重新编程炎性单核细胞， 中性粒细胞，以限制损伤和增强再生。

Summary: Regeneration of tissues following injury can be limited due to the development of strong inflammatory responses that can lead to substantial cell death and inappropriate conditioning of the local environment, which becomes deficient in stimulatory factors and has an excess of inhibitory factors. Our long-term goal is to develop nanoparticles that reprogram the phenotype of monocytes and neutrophils in the blood after trauma, resulting in altered trafficking and anti-inflammatory phenotypes that reduce the extent of damage and may support an environment that leads to enhanced regeneration. The premise of the proposed research is based on our preliminary data indicating the ability to deliver nanoparticles in a minimally invasive manner that target inflammatory monocytes and neutrophils in the blood to reprogram their function, which leads to substantial functional recovery in a spinal cord model. The particles may enhance recovery by multiple mechanisms, including reducing immune cell accumulation at the injury, modulating the splenic microenvironment that is known to coordinate inflammatory responses, or directly inducing an anti-inflammatory or pro-regenerative environment at the injury. The following aims employ nanoparticles with differential binding to monocytes and neutrophils, which influences their phenotype such as trafficking and cytokine production. Importantly, the reprogramming is mediated solely by the physicochemical properties of the nanoparticles (e.g., size, charge, composition) and does not involve an active pharmaceutical ingredient (API), which have been discontinued from many applications due to the risk-benefit ratio. The focus herein is to identify the mechanism by which the particles are enhancing functional recovery, which may also identify design parameters that are more efficient. Aim 1 will investigate nanoparticle association with innate immune cells in circulation, and their subsequent trafficking and phenotype in the inflammatory response. Nanoparticle injection following SCI has led to substantial recovery gains we aim to identify the mechanisms by which the particles are promoting recovery. Particles that induce differential binding, phenotypic polarization, and trafficking of monocytes and neutrophils will be investigated. Aim 2 will investigate the impact of the reprogrammed immune cells on the microenvironment within the spleen and spinal cord. Stromal and immune cells are initially investigated throughout recovery, and we subsequently investigate the extent of axon growth, myelination, and functional recovery. Collectively, these studies will determine the relationship between nanoparticle properties, immune modulation, and the capacity of the environment to reduce damage and enhance functional recovery. We propose that the particles that reprogram based on their physicochemical properties have the potential to be a transformational therapy for trauma by providing a readily available, non-invasive means to reprogram inflammatory monocytes and neutrophils in order to limit damage and enhance regeneration.