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

项目摘要/摘要 Day Lab设计了具有独特物理化学性质的纳米颗粒(NPs)，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的水平。我们开发的NPS通过以下方式实现高精度治疗：(1)提供 对细胞产生拮抗抗体或核酸，以抑制推动疾病进展的基因，(2)提供热量 或其他仅对病变细胞的有效载荷，以响应组织穿透近红外光的激活，或 (3)使用细胞衍生的膜作为涂层，最大限度地减少免疫，从而促进细胞特有的货物运输 识别并启用目标单元格绑定。我们正在应用我们的技术来管理侵袭性癌症， 血液紊乱和孕产妇/胎儿健康状况。此外，我们正在通过严谨的研究证明， NPs中包装的内容和包装方式决定了治疗效果。我们的大部分工作都在推进 过去五年的纳米医学是由Mira计划资助的。展望未来，我们将利用我们获得的 探索纳米医学悬而未决问题的工具和知识，提高纳米粒子的超越能力 生物障碍。 目前，纳米药物的临床前和临床表现之间存在着不受欢迎的差异。 这是由限制NP递送效率、有效性和安全性的生物障碍推动的。其中包括免疫 屏障(导致巨噬细胞清除的蛋白质电晕形成)、血管屏障(有限外渗)、 和组织屏障(不能穿透细胞外基质、粘液等到达所需细胞 异质种群)。在未来五年，我们将通过以下途径解决这些生物障碍 结合和调整我们实验室以前开发的NP的机械性研究，以增强交付和 功效。具体地说，我们将调查与蛋白质日冕介导的免疫清除有关的问题， 炎症在NP渗出中的作用以及NP与生殖组织屏障和阴道的相互作用 微生物组。回答这些问题将指导NPs的发展，提高临床表现。 除了推进更广泛的纳米医学领域，所获得的信息将导致长期 日间实验室研究纳米药物的细胞外和细胞内障碍。总的来说，我们的 这项工作具有基本的科学意义和翻译意义，我们的发现将改变 纳米医学通过开发具有无与伦比的临床性能的技术来解决不同的医疗问题。

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.