CAREER: Engineering the nanoparticle interface for tunable biomolecular aggregation

非技术性总结当你头痛或其他轻微疼痛时，你会服用药片来感觉更好。一旦吞下，药丸使其方式到你的胃和释放一种活性药物，在那里它可以进入你的血液和开始减轻你的疼痛和痛苦。一种简单的药物可以治疗许多不同的疼痛，而不管疼痛的具体原因。治疗许多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。如果药物能专门针对疾病的来源，而不是在身体的其他部位积累，那么其中一些副作用是可以避免的。纳米级材料，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，使用纳米粒子治疗影响国民健康的无数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质将纳米颗粒识别为异物。并非血液中存在的所有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。该项目探索了我们体内天然存在的糖分子可用于选择性地在纳米颗粒表面积累蛋白质的方式。在糖修饰的纳米颗粒上选择性地构建蛋白质层将有助于逃避免疫识别，并作为能够去除与疼痛有关的蛋白质的无药物材料。将教育活动与该研究计划相结合，旨在增加纳米技术职业中女性和代表性不足的群体的招聘和保留。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，为中学生开发教学计划和视频，以及同行指导计划。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进展。现有的减轻不需要的细胞因子的策略依赖于活性药物靶向这些细胞因子上游的途径。活性药物可在脱靶组织中积累，或可能具有广泛作用的效应，导致进一步的并发症，突出了对控制炎症环境中细胞因子生物利用度的新策略的需求。纳米粒可用于递送活性药物，与单独使用药物相比，脱靶并发症较少。即使如此，通过过滤器官和免疫细胞响应于血清蛋白在NP表面上的聚集而去除NP，所述NP表面包括生物分子冠。虽然生物分子冠的形成是用于治疗性治疗的NP设计中的已知障碍，但该提议将建立一套新的生化工具，以通过使用对炎性细胞因子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，以选择性地形成NP生物分子冠。为此，将探索三个具体的推力：1）部署硫酸化多糖以通过胜过NP上的血清蛋白质聚集来选择性地构建生物分子冠，2）工程化生物分子冠形成以选择性地隔离炎性细胞因子，以及3）通过吞噬装饰有定制的生物分子冠的NP来诱导细胞摄取以永久地去除与NP结合的炎性细胞因子。拟议的研究将确定多糖硫酸化模式如何控制生物分子冠的形成和纳米材料的吞噬作用，并在工程新型纳米医学方法治疗多种疾病方面具有潜在的应用。这些基础研究与教育活动的整合将提供深入接触纳米技术领域，以及同行指导，使招聘和保留妇女和学生从代表性不足的群体在不断增长的领域nanotechnologyThis奖反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.