Surface-functionalized nanoparticle adjuvants for pulmonary immune modulation

4.肺免疫调节的表面功能化纳米粒佐剂。 项目负责人：凯瑟琳·弗罗门(CBE) 呼吸道疾病影响着全球数百万人，需要新的进展来 改进预防和治疗方案。吸入性疫苗已经显示出显著的 功效，提供器官特异性反应和跨替代粘膜的普遍保护 以改善屏障保护。然而，开发高效、经济高效的免疫- 由于缺乏黏膜特异性佐剂，吸入的调节性治疗仍然难以实现。 能够提供精确的分子线索，产生高度受调控的免疫反应。 为了满足这一需求，我们将开发基于纳米颗粒(NP)的佐剂，专门用于吸入性 并确定导致受控肺免疫模式的物理化学特征。 受分子相互作用的启发，我们将告知NP佐剂的分子设计，以提供 精确的信号提示引导特异性T辅助细胞1(TH1)、TH2和TH17免疫反应 肺，创造精确的NPs，使相关新病原体的最佳输送成为可能 分子模式(PAMP)配体。在明矾作为TH2佐剂的历史成功的基础上，我们 将利用金属有机骨架固有的低密度和规则有序的结构 (MOF)纳米粒子生成一类新型的含铝多孔MOF佐剂和 评估它们在肺内的结构-功能佐剂反应。同时，我们将评估 这些化合物和聚合物基佐剂NPs的特定物理化学性质在阐明其作用方面的作用 表面净电荷、侧链化学物种、NP降解率和PAMP配体的作用 价态(包括由Grimes提出的高度纯化的细菌肽多糖信号分子 在第一阶段)在驱动特定的佐剂反应中。这项研究的总体科学成果 项目将是1)产生一个具有精确分子设计的新的佐剂文库2) 对我们的肺特异性预防性疫苗和免疫佐剂系统的评估 调整疗法，以及3)建立一套关于以下方面的工作设计规则 用于肺部治疗的物理化学NP特性。拟议的研究将广泛地 提高对佐剂NP相互作用的基本理解，并在分子水平上提供信息 肺部应用的设计规则。

4. Surface-functionalized nanoparticle adjuvants for pulmonary immune modulation. Project Leader: Catherine Fromen (CBE) Respiratory diseases impact millions of people worldwide and novel advances are needed to improve prophylactic and treatment options. Inhalable vaccines have demonstrated notable efficacy, providing organ-specific responses and universal protection across alternative mucosa for improved barrier protection. However, development of efficient, cost-effective immune- modulatory therapies for inhalation remains elusive, owing to a lack of mucosal-specific adjuvants capable of delivering of precision molecular cues that yield highly regulated immune responses. To address this need, we will develop nanoparticle (NP)-based adjuvants specifically for inhalable delivery and identify the physiochemical features that lead to controlled lung immune profiles. Inspired by molecular interactions, we will inform the molecular design of NP adjuvants to provide precise signaling cues that direct specific T helper 1 (TH1), TH2, and TH17 immune responses in the lung, creating precision NPs that enable optimized delivery of novel pathogen associated molecular pattern (PAMP) ligands. Building on historical success of alum as a TH2 adjuvant, we will leverage the inherent low density and regularly ordered structure of metal organic framework (MOF) NPs to generate a novel class of porous aluminum-containing MOF adjuvants and evaluate their structure-functional adjuvant responses in the lung. In parallel, we will evaluate the role of specific physiochemical properties of these and polymeric-based adjuvant NPs to elucidate the role of net surface charge, pendant chemical species, NP degradation rate, and PAMP ligand valency (including highly purified bacterial peptidoglycan signaling molecules proposed by Grimes during Phase I) in driving specific adjuvant responses. The overall scientific outcomes of this project will be 1) generation of a new library of adjuvants with precise molecular designs 2) evaluation of our adjuvant systems for both lung-specific prophylactic vaccination and immune modulating therapies, and 3) establishment of a working set of design rules in regards to physiochemical NP properties for pulmonary therapeutics. The proposed studies will broadly improve fundamental understanding of adjuvant NP interactions and inform molecular-level design rules for pulmonary applications.