CAREER: Engineering the nanoparticle interface for tunable biomolecular aggregation

非技术总结当你头痛或其他轻微的疼痛或疼痛时，你会吃一片药来感觉好一些。一旦吞咽，这种药丸就会进入你的胃，释放出一种活性药物，在那里它可以进入你的血液，开始减轻你的疼痛。一种简单的药物可以治疗许多不同的疼痛，无论疼痛的具体原因是什么。治疗多种不同疾病的能力具有优势，但也会导致一长串潜在的副作用。如果药物专门针对疾病的源头，而不是累积在身体的其他部位，其中一些副作用是可以避免的。纳米材料，如纳米颗粒，可以防止药物在健康组织中积累，从而限制副作用。问题是，使用纳米颗粒治疗无数影响国民健康的疾病目前受到你自己的免疫系统的阻碍。你的免疫系统通过使用血液中存在的某些免疫识别蛋白来识别纳米颗粒是异物。并不是所有存在于血液中的蛋白质都参与免疫识别，这些“好”蛋白质的选择性积累可能有助于逃避免疫细胞。该项目探索体内天然存在的糖分子如何被用来选择性地在纳米颗粒表面积聚蛋白质。在糖修饰的纳米颗粒上选择性地建立蛋白质层将用于逃避免疫识别，以及作为一种能够去除与疼痛有关的蛋白质的无药物材料。将教育活动与这一研究方案相结合，旨在增加纳米技术职业中妇女和代表性不足群体的招聘和留住。教育活动包括为高中生举办的研讨会，展示我们日常生活中使用的纳米材料背后的科学，为中学生开发教学程序和视频，以及同伴指导计划。技术摘要本提案旨在设计聚合物纳米颗粒(NP)，通过操纵NP在生物系统中的界面行为来管理细胞因子的生物利用度。细胞因子指导细胞，但异常细胞因子的存在会加剧疾病的进展。现有的减轻有害细胞因子的策略依赖于活性药物来靶向这些细胞因子的上游通路。活性药物可在非靶标组织中积聚，或可能具有广泛的作用效应，导致进一步的并发症，突显出需要新的策略来管理炎症环境中细胞因子的生物利用度。NPS可用于提供活性药物，与单独使用药物相比，导致较少的非靶向并发症。即使如此，过滤器官和免疫细胞也会对构成生物分子日冕的NP表面的血清蛋白聚集做出反应，从而去除NP。虽然生物分子电晕的形成是NP设计用于治疗的已知障碍，但这一提议将建立一套新的生化工具来利用生物分子电晕作为治疗剂，通过使用与炎症细胞因子具有很强结合亲和力的硫化多糖选择性地形成NP生物分子电晕。为此，将探索三个特定的推力：1)部署硫酸多糖，通过竞争对手血清蛋白质在NPs上的聚集来选择性地构建生物分子电晕，2)设计生物分子电晕形成，选择性地隔离炎性细胞因子，以及3)通过吞噬装饰有定制生物分子冠状结构的NPs来诱导细胞摄取，永久地去除与NPs结合的炎性细胞因子。这项拟议的研究将确定多糖硫化模式如何控制纳米材料的生物分子电晕形成和吞噬作用，并可能应用于设计治疗几种疾病的新型纳米医学方法。将这些基础性研究与教育活动相结合，将提供对纳米技术领域的深入了解，以及同行指导，以招聘和留住纳米技术增长领域中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势和更广泛的影响审查标准进行评估，被认为值得支持。

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.