Design of RNA-triggered Disassembly Mechanisms in Multi-responsive Polymer Nanocapsules for Personalized Physiological Profiling and Tailored Therapeutics

非技术：该奖项将开发新方法，以识别患病组织中的特定基因图谱，随后仅在目标组织中释放“个性化”药物鸡尾酒或诊断分子。定位和治疗病变组织的一种方法是注射含有药物的纳米颗粒，这些纳米颗粒将在体内循环，直到它们与病变细胞接触。纳米颗粒可以被设计成在细胞内分解并释放包裹的药物；然而，为了保护健康细胞不受药物的影响，有必要设计出只在患病细胞中分解的纳米颗粒。这项研究将设计和生产由DNA“双链”连接在一起的聚合物纳米颗粒，其序列部分互补。这种双链化合物将被设计成只有在完全互补的DNA或RNA链存在的情况下才会分解，从而导致纳米颗粒的分解和任何被封装的化合物的释放。PIs将生产dna连接的纳米颗粒，设计用于在乳腺癌特异性RNA分子存在时分解，并且将测试这些纳米颗粒是否只在癌细胞内选择性地释放模型药物（染料）。教育工作、实习和研讨会旨在增加特拉华大学研究活动中代表性不足的学生的参与度和入学率。技术方面：这项研究解决了美国国家工程院的大挑战，即通过开发新方法来设计更好的药物，最终可以快速评估患者的基因图谱并发布个性化药物鸡尾酒。pi的方法是在聚合物纳米载体中结合DNA“链位移”生物传感设计，使DNA界面控制纳米载体的稳定性。识别特定的RNA或DNA序列将导致链位移反应，使纳米载体不稳定，并允许释放封装的药物或诊断。这项工作的主要里程碑包括设计对乳腺癌特异性rna敏感的DNA链位移设计；这些DNA双链在聚合物胶束内的结合；建立rna介导的纳米载体分解的特异性和有效性；在纳米载体表面添加癌细胞靶向肽；在乳腺癌细胞中建立选择性的细胞摄取和有效的货物（染料）释放。教育活动将包括高中实习、毕业生招聘研讨会，以及针对代表性不足群体的指导工作，通过pi参与ACS SEED、SWE、工程女性和ACS学者计划等项目来促进。

Nontechnical:This award will develop new methods to identify specific genetic profiles in diseased tissues and subsequently release "personalized" drug cocktails or diagnostic molecules only within the targeted tissues. One way to locate and treat diseased tissues is by injecting drug-containing nanoparticles that will circulate through the body until they come into contact with diseased cells. Nanoparticles can be designed to fall apart inside of cells and release encapsulated drugs; however, to protect healthy cells from receiving the drug, it is necessary to design nanoparticles that only fall apart in diseased cells. This research will design and produce polymer nanoparticles linked together by DNA "duplexes" whose sequences are partially complementary. The duplexes will be designed to unbind only in the presence of a fully complementary strand of DNA or RNA, leading to the disassembly of the nanoparticles and the release of any encapsulated compounds. The PIs will produce DNA-linked nanoparticles designed to disassemble in the presence of breast cancer-specific RNA molecules, and will test whether these nanoparticles will selectively release model drugs (dyes) only within cancer cells. Educational efforts, internships and workshops are aimed at increasing participation and enrollment of underrepresented students in research activities at the University of Delaware.Technical:This research addresses the National Academy of Engineering's Grand Challenge to engineer better medicines by developing new approaches that will ultimately allow rapid assessment of the genetic profiles in patients and the release of personalized drug cocktails. The PIs approach is to incorporate DNA "strand displacement" biosensing designs within polymer nanocarriers such that the DNA interface controls nanocarrier stability. Recognition of specific RNA or DNA sequences will result in a strand displacement reaction that destabilizes the nanocarrier and allows the release of encapsulated drugs or diagnostics. The major milestones in this work include the design of DNA strand displacement designs sensitive to breast cancer-specific RNAs; incorporation of these DNA duplexes within block polymer micelles; establishment of the specificity and efficacy of RNA-mediated nanocarrier disassembly; addition of cancer cell-targeting peptides on the surface of the nanocarriers; and establishment of selective cellular uptake and efficient cargo (dye) release in breast cancer cells. Educational activities will include high school internships, graduate recruitment workshops, and mentoring efforts targeted at underrepresented groups, facilitated through the PIs involvement in programs including ACS SEED, SWE, Women in Engineering, and the ACS Scholars Program.