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

探索纳米/生物相互作用，以了解和克服限制纳米医学的生物障碍

• 批准号: 10623828
• 负责人: Emily S Day
• 金额: $ 40.8万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623828
• 关键词: Address; Antibodies; Architecture; Artificial nanoparticles; Binding; Biological; Blood Vessels; COVID-19; Cells; Clinical; Development; Disease; Disease Management; Disease Progression; Disparity; Extracellular Matrix; Extravasation; Fetal health; Funding; Genes; Goals; Healthcare; Hematological Disease; Immune; Inflammation; Knowledge; Lead; Light; Macrophage; Malignant Neoplasms; Mediating; Membrane; Mucous body substance; Nucleic Acids; Patient-Focused Outcomes; Penetration; Performance; Population Heterogeneity; Precision therapeutics; Property; Proteins; Quality of life; Research; Role; Safety; Technology; Therapeutic; Tissues; Treatment Efficacy; Whole Organism; Work; biological systems; extracellular; immune clearance; improved; nano; nanomedicine; nanoparticle; nanoparticle delivery; novel strategies; pre-clinical; programs; reproductive; response; therapeutic nanoparticles; tool; vaginal microbiome; Address; Antibodies; Architecture; Artificial nanoparticles; Binding; Biological; Blood Vessels; COVID-19; Cells; Clinical; Development; Disease; Disease Management; Disease Progression; Disparity; Extracellular Matrix; Extravasation; Fetal health; Funding; Genes; Goals; Healthcare; Hematological Disease; Immune; Inflammation; Knowledge; Lead; Light; Macrophage; Malignant Neoplasms; Mediating; Membrane; Mucous body substance; Nucleic Acids; Patient-Focused Outcomes; Penetration; Performance; Population Heterogeneity; Precision therapeutics; Property; Proteins; Quality of life; Research; Role; Safety; Technology; Therapeutic; Tissues; Treatment Efficacy; Whole Organism; Work; biological systems; extracellular; immune clearance; improved; nano; nanomedicine; nanoparticle; nanoparticle delivery; novel strategies; pre-clinical; programs; reproductive; response; therapeutic nanoparticles; tool; vaginal microbiome

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.

项目摘要/摘要 具有独特物理化学特性的日期实验室工程师纳米颗粒（NP） 治疗各种疾病，并通过研究纳米/生物相互作用来阐明建筑如何影响功能 从亚细胞到整个生物水平。我们开发的NP可以通过：（1）提供高精度治疗 对细胞的拮抗抗体或核酸抑制驱动疾病进展的基因，（2）提供热量 或其他有效载荷仅针对患病细胞，以响应于组织 - 渗透近红外光的激活，或 （3）通过使用细胞来源的膜作为涂层，促进细胞特异性货物的递送，从而最大程度地减少免疫力 识别并启用靶细胞结合。我们正在运用我们的技术来管理激进的癌症， 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 NP中包装的内容及其包装方式决定了治疗效力。我们的大部分工作 在过去五年中，纳米医学是由MIRA计划资助的。向前迈进，我们将使用我们获得的 工具和知识以探测纳米医学中未解决问题的问题，并提高NP超越的能力 生物障碍。 纳米药物的临床前和临床性能之间存在不希望的差异 这是由限制NP输送效率，功效和安全性的生物障碍驱动的。这些包括免疫 障碍物（蛋白质电晕的形成导致巨噬细胞清除率），血管屏障（有限的外渗）， 和组织屏障（通过细胞外基质，粘液等穿透较差，以达到所需的细胞 异构种群）。在接下来的五年中，我们将通过 机械研究纳入了以前在我们实验室中开发的NP，以增强交付和 功效。具体而言，我们将研究与蛋白质电晕介导的免疫清除相关的问题， 炎症在NP渗出中的作用，以及与生殖组织屏障和阴道的NP相互作用 微生物组。回答这些问题将指导NP的发展，并提高临床性能。 除了推进纳米医学的更广泛领域外，获得的信息还将导致长期 对纳米医学的细胞外和细胞内屏障的研究。总体而言，我们的 工作具有基本的科学和翻译意义，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来解决各种医疗保健问题的纳米医学。