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.

非技术摘要当您患有标头或其他轻微的酸痛或疼痛时，您会服用药丸来感觉更好。吞咽后，该药会进入您的摊位，并释放一种活跃的药物，在那里它可以进入您的血液，并开始减轻您的酸痛和疼痛。一种简单的药物可以治疗多种不同的酸痛和疼痛，而不论疼痛的特定原因如何。治疗许多不同条件的能力具有优势，但也导致了很长的潜在副作用。如果该药物专门针对该疾病的来源，而不是在身体其他部位的丙烯酸，则可以避免其中一些副作用。纳米尺度材料（例如纳米颗粒）可以防止药物在健康组织中的积累，从而限制副作用。问题在于，目前，您自己的免疫学系统阻碍了使用纳米颗粒来治疗影响民族健康的无数疾病。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。并非所有参与免疫识别的血液中存在的蛋白质，这些“良好”蛋白质的选择性积累都可以有助于逃避免疫细胞。该项目投射了自然发生在我们体内的糖分子的方式，可用于在纳米颗粒表面有选择性地丙烯酸蛋白。在糖装饰纳米颗粒上的蛋白质层的选择性建造将有助于逃避免疫识别，并用作能够去除涉及疼痛的蛋白质的无药物材料。将教育活动与该研究计划的整合是设计旨在增加妇女和纳米技术职业中代表性不足的群体的招聘和保留。教育活动包括针对高中生的研讨会，以展示我们日常生活中使用的纳米材料背后的科学，教学计划的开发和中学学生的视频以及同伴的心态计划。技术摘要旨在通过控制细胞因子生物学的互动式行为，旨在设计聚合物纳米粒子（NPS）。细胞因子指示细胞，但异常的细胞因子的存在加剧了疾病的进展。减轻不良细胞因子的现有策略依靠活性药物来靶向这些细胞因子上游的途径。活性药物可以在脱靶时机积累，或者可能产生广泛的作用，从而导致进一步的并发症，这突出了需要在炎症环境中对细胞因子生物利用度进行治疗的新型策略的需求。 NP可用于输送活性药物，与单独的药物相比，导致脱靶并发症较少。即便如此，通过响应包括构成生物分子电晕的NP表面上的血清蛋白聚集，通过过滤器官和免疫细胞进行过滤器官和免疫细胞去除NP。虽然形成生物分子电晕是NP设计中的已知障碍，但该建议将建立一套新的生化工具，通过使用硫化多聚糖果的硫化多糖为炎症性抑制剂，可用于选择性地构建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) Induced cellular uptake via phagocytosis of NPs adorned with tailored biomolecular coronas to permanently去除与NP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纳米材料的生物分子电晕形成和吞噬作用，并在工程新型纳米医学方法中的潜在应用来治疗多种疾病。这些基本研究与教育活动的整合将为纳米技术领域提供深入的接触，以及在纳米技术领域不断增长的妇女和学生的招聘和留住妇女和学生的招聘和保留，这反映了NSF的法定任务，并通过评估构成的构成师的支持者，这一奖项反映了构成群体的影响力，并反映了构成的构成。