CAREER: Engineering the nanoparticle interface for tunable biomolecular aggregation

职业：设计纳米颗粒界面以实现可调节的生物分子聚集

• 批准号: 2338117
• 负责人: Courtney Dumont
• 金额: $ 65.12万
• 依托单位: University of Miami
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-07-01 至 2029-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2338117&HistoricalAwards=false
• 关键词: CAREER; Engineering; nanoparticle; interface; tunable

Non-Technical SummaryWhen you have a headache or other minor aches or pain, you take a pill to feel better. Once swallowed, the pill makes its way to your stomach and releases an active drug, where it can enter your bloodstream and begin to lessen your aches and pains. One simple drug can treat numerous different aches and pains, regardless of the specific cause of the pain. The ability to treat many different conditions has advantages, but it also results in a long list of potential side effects. Some of these side-effects could be avoided if the drug would specifically target the source of the condition, and not accumulate in other parts of the body. Nanometer-scale materials, such as nanoparticles, can prevent drug accumulation in healthy tissues, thereby limiting side effects. The problem is that the use of nanoparticles to treat a myriad of diseases that impact national health is currently hampered by your own immune system. Your immune system recognizes nanoparticles as a foreign body by using certain immune recognition proteins present in the blood. Not all proteins present in blood participate in immune recognition, and the selective accumulation of these “good” proteins can potentially aid in evading immune cells. This project probes the way in which sugar molecules that naturally occur in our bodies can be used to selectively accumulate proteins on the nanoparticle surface. The selective building of protein layers on the sugar-decorated nanoparticles will serve to evade immune recognition, as well as serve as a drug-free material capable of removing proteins that are involved in pain. Integration of educational activities with this research program are design to increase recruitment and retention of women and under-represented groups in nanotechnology careers. Educational activities include workshops for high school students to showcase the science behind nanomaterials used in our daily lives, development of instructional programs and videos for middle school students, and peer mentorship programs.Technical SummaryThis proposal aims to engineer polymeric nanoparticles (NPs) that govern cytokine bioavailability through manipulation of the interfacial behavior of the NP within biological systems. Cytokines instruct cells, but aberrant cytokine presence exacerbates disease progression. Existing strategies to mitigate unwanted cytokines rely on active drugs to target pathways upstream of these cytokines. Active drugs can accumulate in off-target tissues or may have broad-acting effects resulting in further complications, highlighting the need for novel strategies to govern cytokine bioavailability in the inflammatory milieu. NPs can be used to deliver active drugs, resulting in fewer off-target complications compared to the drug alone. Even still, NPs are removed by filtering organs and immune cells in response to the aggregation of sera proteins on the NP surface that comprise the biomolecular corona. While formation of the biomolecular corona is a known roadblock in NP design for therapeutic treatment, this proposal will establish a new set of biochemical tools to leverage the biomolecular corona as a therapeutic agent by using sulfated polysaccharides with strong binding affinity for inflammatory cytokines to selectively form the NP biomolecular corona. To do so, three specific thrusts will be explored: 1) Deploy sulfated polysaccharides to selectively build the biomolecular corona by outcompeting sera protein aggregation on NPs, 2) Engineer biomolecular corona formation to selectively sequester inflammatory cytokines, and 3) Induce cellular uptake via phagocytosis of NPs adorned with tailored biomolecular coronas to permanently remove inflammatory cytokines bound to the NPs. The proposed research will identify how polysaccharide sulfation patterns control biomolecular corona formation and phagocytosis of nanomaterials, with potential applications in engineering novel nanomedicine approaches for treatment of several diseases. Integration of these foundational studies with educational activities will provide in-depth exposure to the field of nanotechnology, as well as peer mentoring to enable recruitment and retention of women and students from under-represented groups in the growing field of nanotechnologyThis award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

非技术摘要当您出现头痛或其他轻微疼痛或疼痛时，您可以服用药丸来感觉好一点，一旦吞下，药丸就会进入您的胃并释放出活性药物，药物可以进入您的血液并开始减轻。一种简单的药物可以治疗多种不同的疼痛，无论疼痛的具体原因如何，治疗多种不同病症的能力都有其优势，但它也会导致一长串潜在的副作用。这些副作用可能如果药物专门针对疾病的根源，并且不会在身体的其他部位积聚，则可以避免药物在健康组织中积聚，从而限制副作用。使用纳米颗粒治疗影响国民健康的多种疾病目前受到您自身免疫系统的阻碍，您的免疫系统通过使用血液中存在的某些免疫识别蛋白将纳米颗粒识别为异物。免疫识别，以及这些“好”蛋白质的选择性积累可能有助于逃避免疫细胞，该项目探讨了如何利用我们体内自然存在的糖分子在纳米颗粒表面选择性地积累蛋白质。糖修饰的纳米颗粒将有助于逃避免疫识别，并作为一种无药物材料，能够去除与疼痛有关的蛋白质，将教育活动与该研究计划相结合，旨在增加女性和女性的招募和保留。教育活动包括为高中生举办研讨会，展示我们日常生活中使用的纳米材料背后的科学，为中学生开发教学计划和视频，以及同伴计划。技术导师摘要该提案旨在工程聚合物纳米颗粒（NP）通过操纵生物系统内纳米颗粒的界面行为来控制细胞因子的生物利用度，但细胞因子的异常存在会加剧疾病的进展。不需要的缓解性细胞因子依赖于活性药物来靶向这些细胞因子的上游途径，活性药物可能会在非目标组织中积聚，或者可能产生广泛的作用，导致进一步的并发症，这突出表明需要新的策略来控制炎症环境中的细胞因子生物利用度。纳米粒子可用于递送活性药物，与单独使用药物相比，纳米粒子可通过过滤器官和免疫细胞来响应纳米粒子表面的血清蛋白聚集而被去除。虽然生物分子冠的形成是纳米粒子治疗设计中的一个已知障碍，但该提案将建立一套新的生化工具，通过使用具有强结合亲和力的硫酸化多糖来利用生物分子冠作为治疗剂。为了使炎症细胞因子选择性地形成 NP 生物分子冠，我们将探索三个具体的方向：1) 使用硫酸化多糖。通过击败纳米颗粒上的血清蛋白聚集来选择性地构建生物分子冠，2) 设计生物分子冠的形成以选择性地隔离炎症细胞因子，以及 3) 通过吞噬装饰有定制生物分子冠的纳米颗粒来诱导细胞摄取，以永久去除与纳米颗粒结合的炎症细胞因子拟议的研究将确定多糖硫酸化模式如何控制生物分子纳米材料的电晕形成和吞噬作用，在工程治疗多种疾病的新型纳米医学方法中具有潜在的应用，这些基础研究与教育活动的结合将提供对纳米技术领域的深入接触，以及同行指导，以实现招募和培训。在不断发展的纳米技术领域保留来自代表性不足群体的妇女和学生该奖项反映了 NSF 的法定使命，并通过使用基金会的智力优点和更广泛的影响审查标准进行评估，被认为值得支持。