Probing nano/bio interactions to understand and overcome biological barriers limiting nanomedicine

项目概要/摘要 天实验室工程师纳米粒子（纳米粒子）具有独特的物理化学性质，以改变 治疗各种疾病，并通过研究纳米/生物相互作用阐明结构如何影响功能 从亚细胞到整个生物体水平。我们开发的NP通过以下方式实现高精度治疗：（1）提供 拮抗抗体或核酸的细胞，以抑制基因，驱动疾病的进展，（2）提供热量 或其它有效载荷仅响应于用穿透组织的近红外光激活而作用于患病细胞，或 (3)通过使用细胞衍生的膜作为涂层来促进细胞特异性货物递送， 识别并使靶细胞结合。我们正在应用我们的技术来管理侵袭性癌症， 血液疾病和母亲/胎儿健康状况。此外，我们通过严格的研究证明， 什么被包装在NP中以及如何包装决定了治疗效力。我们的大部分工作 在过去的五年里，纳米医学是由MIRA计划资助的。今后，我们将利用我们获得的 工具和知识，以探索纳米医学中未回答的问题，并提高纳米粒子的能力，以超越 生物屏障。 目前，纳米医学的临床前和临床性能之间存在不期望的差异 这是由限制NP递送效率、功效和安全性的生物屏障驱动的。其中包括免疫 屏障（蛋白质冠形成导致巨噬细胞清除），血管屏障（有限外渗）， 和组织屏障（难以穿透细胞外基质、粘液等到达细胞外基质中的所需细胞）。 异质种群）。在接下来的五年里，我们将通过以下方式解决这些生物障碍： 机制研究，纳入和适应纳米粒子以前在我们的实验室开发，以提高交付和 功效具体来说，我们将研究与蛋白质冠介导的免疫清除， 炎症在NP外渗中的作用以及NP与生殖组织屏障和阴道的相互作用 微生物组解决这些问题将指导开发具有改善临床性能的NP。 除了推进更广泛的纳米医学领域，获得的信息将导致长期 研究日实验室解决细胞外和细胞内的障碍纳米医学。总体而言，我们 工作具有基本的科学意义和转化意义，我们的发现将改变 通过开发具有无与伦比的临床性能的技术，将纳米医学应用于各种医疗保健问题。

PROJECT SUMMARY/ABSTRACT The Day Lab engineers nanoparticles (NPs) with unique physicochemical properties to transform the treatment of various diseases and elucidates how architecture impacts function by studying nano/bio interactions from the subcellular to whole organism level. The NPs we develop enable high precision therapy by: (1) delivering antagonistic antibodies or nucleic acids to cells to inhibit genes that drive disease progression, (2) supplying heat or other payloads only to diseased cells in response to activation with tissue-penetrating near-infrared light, or (3) facilitating cell-specific cargo delivery by using cell-derived membranes as coatings that minimize immune recognition and enable target cell binding. We are applying our technologies to manage aggressive cancers, blood disorders, and maternal/fetal health conditions. Further, we are proving through rigorous studies that both what is packaged in NPs and how it is packaged dictate therapeutic potency. Much of our work advancing nanomedicine over the last five years was funded by the MIRA program. Moving forward, we will use our acquired tools and knowledge to probe unanswered questions in nanomedicine and advance the ability of NPs to surpass biological barriers. There is currently an undesired disparity between preclinical and clinical performance of nanomedicines that is driven by biological barriers that limit NP delivery efficiency, efficacy, and safety. These include immune barriers (protein corona formation leading to macrophage clearance), vascular barriers (limited extravasation), and tissue barriers (poor penetration through extracellular matrix, mucus, etc. to reach desired cells in heterogeneous populations). Over the next five years we will address these biological barriers through mechanistic studies that incorporate and adapt NPs previously developed in our lab to enhance delivery and efficacy. Specifically, we will investigate questions related to protein corona-mediated immune clearance, the role of inflammation in NP extravasation, and NP interaction with reproductive tissue barriers and the vaginal microbiome. Answering these questions will guide the development of NPs with improved clinical performance. In addition to advancing the broader field of nanomedicine, the information gained will lead into the long-term research of the Day Lab addressing both extracellular and intracellular barriers to nanomedicine. Overall, our work has both basic scientific and translational significance, and our discoveries will transform the application of nanomedicine to diverse healthcare problems by developing technologies with unmatched clinical performance.