Functional Materials Through Synthesis Informed Design

Stanford University, Stanford CA

Investigators

Abstract

With this award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Paul Wender of the Department of Chemistry at Stanford University. Professor Wender and his coworkers are investigating the design, synthesis, characterization, and evaluation of new materials that complex, protect, deliver, and release negatively-charged cargos such as RNA and DNA inside of living cells. These cargos are of unsurpassed importance in life science research, and these studies have potential utility in understanding cancer, protein therapy, allergy tolerization, neuroscience, universal flu vaccine development, disease detection and gene editing. These new materials are first-of-their-kind positively-charged carriers, designed to electrostatically grab on to the negatively-charged cargos. After cell entry, the positively-charged carriers change their physical properties, dynamically losing their positive charge and thereby releasing their negatively-charged cargo. The released RNA/DNA cargos contain a molecular message that is then translated by cellular machinery to produce proteins with research, diagnostic and other benefits. Coworkers trained in this program are becoming the next generation of scientific thought leaders and educators, joining over 300 former coworkers of Professor Wender who are now in leading positions in academia and the biotechnology industry. Many are also involved with science education at the college and high school levels. Professor Wender is also hosting visits from high school students, providing input on science projects, and lecturing at several science-for-non-scientist events. He has pioneered a new undergraduate course on scientific communication and innovation (SCI) (https://news.stanford.edu/2017/11/30/undergraduates-start-popular-science-publication/), engaging undergraduates in teaching high school and college students about science. This has led to a new undergraduate organization that is sharing and celebrating the fun, excitement and value of science through their web site and other media (https://fascinatepublication.org). In this project, Professor Wender is studying the design, synthesis, and evaluation of new dynamic functional materials for the delivery of probes, imaging agents, catalysts, and other cargo across biological barriers. To accomplish this, he is developing new reactions, reagents, and catalysts for synthesis, and developing machine learning for retrosynthetic analysis and material design. The intellectual foundation of these studies is intrinsically chemical - synthesis, computer learning, and materials science, with potentially profound consequences in life science research. Increasingly in chemistry and in Professor Wender's research, mechanistic and synthetic chemistry have been integrated into studies directed at the design, synthesis and evaluation of functional materials of scientific and societal value (e.g. catalysts, imaging agents, sensors, molecular machines, diagnostics, drug delivery systems). The proposed research is primarily directed at the design, synthesis and evaluation of dynamic materials that complex, protect, deliver and release in cells polyanions such as RNA and DNA, representing the single most significant bottleneck to the advancement of many new RNA/DNA technologies. In this program, new classes of materials are being studied which serve initially as cations that electrostatically complex polyanions and subsequently change their physical properties, through an O-to-N acyl shift mechanism, thereby converting to neutral byproducts and releasing their polyanionic RNA/DNA cargo. The delivery vehicles, referred to as charge-altering releasable transporters (CARTs), represent a novel challenge in synthesis as unlike most synthetic targets which are selected for their stability, CARTs are designed to degrade. This project is synthesizing unprecedented monomeric, dimeric and dendrimeric CARTs (non-oligomeric CARTs), exploring the factors that influence their performance and the rules for their use in delivering cargos into living cells. These intrinsically chemical and synthetic studies are directed at goals that enable new opportunities in biology, imaging, materials science, and medicine. This 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.