Engineered Protein-Lipid Systems for siRNA and Small Molecule Delivery

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Non-Technical: This award by the Biomaterials program in the Divison of Materials Research to New York University is to develop biomaterials capable of dual gene and drug delivery system, for potential treatment of multi-drug resistant cancer cells. This award is cofunded by Particulate and Multiphase Processes program in the Division of Chemical, Bioengineering, Environmental, and Transport Systems (Directorate for Engineering) and the BioMaPS program. The proposed experiments would lead to the generation of novel agents for biomedicine, and transform the traditional view of therapeutics. These systems will also impact biotechnology as the lessons learned from these studies that can be employed for delivery of other genes and agents with applications extending to non-medical industries including personal care, cosmetics and agriculture. This multidisciplinary research will train the next generation students, scientists and engineers to employ cutting edge technologies in biomaterials, chemistry, engineering and cell biology. In addition to teaching and mentoring graduate students and postdoctoral researchers, the PI will supervise underrepresented undergraduates and high-school students in laboratory research. The PI is also planning to integrate technology and social media into both undergraduate and graduate courses, and exposing these students to cutting-edge research. For outreach, the PI will continue to participate in the Applied Research Innovations in Science and Engineering program in engaging local NYC 10th and 11th grade students to biomaterials research. As director of the Summer Bioengineering Program, the PI will be actively recruiting underrepresented high school students to participate in a biologically inspired materials course.Technical: Nucleic acids and small molecule therapeutics possess critical instructions for controlling biological processes with tangible implications in fundamental cell and organismal studies, biotechnology and medicine. However, the intracellular delivery of nucleic acids and small molecules has been a challenge predominantly due to the plasma membrane barrier. The goal of this project is to develop a multifunctional engineered protein-lipid system (lipoproteoplexes) capable of: 1) effectively complexing with siRNA; 2) encapsulating a small molecule drug (curcumin, doxorubicin, etc.) without the need for covalent modification; and 3) triggering release of the dual payload once inside the cell leading to a programmed cellular outcome. In order to produce a vehicle capable of delivering both gene and therapeutic small molecule, the PI proposes an innovative approach to re-engineer the coiled-coil domain of cartilage oligomeric matrix protein so that it is able to complex with nucleic acids and small molecules in conjunction with lipids based on PI's initial success in introducing positive charge on the surface through protein engineering. Innovations in these engineered lipoproteoplexes include: 1) the ease of integrating mutations enabling rapid optimization; 2) dual drug and gene encapsulation; and 3) control over the delivery and self-assembly. The versatility of the proposed engineered protein-lipid systems will not only prove useful for delivering small molecules and siRNA to treat multi-drug resistant cancers, but also for delivering a variety of chemical agents and genes alone or in combination to gain insight into cell functions.