PART 1: NON-TECHNICAL SUMMARY The goal of this project is to develop and investigate new bioinspired materials that can package and protect gene therapeutics from degradation and enhance their efficacy. Gene therapy, the therapeutic delivery of nucleic acid into a patient's cells as a drug to treat disease, has the potential to be a general treatment for any disease with a genetic determinant. However, protection of genetic cargo from degradation and clearance, as well as delivery to the correct tissue location is a significant challenge. Two major approaches will be applied to produce these new biomaterials: 1) combination of natural components with an artificial scaffold; and 2) modification of natural biomaterial scaffolds with synthetic components. The artificial components are designed to bind gene therapeutics, while the natural components impart targeting function and biocompatibility. The artificial biomaterials will thus mask the presence of the therapeutic cargo, protecting it from degradation. Natural biological components such as sugars and lipids are expected to enhance water-solubility, biocompatibility and targeting of gene therapy to the correct biological target. These new biomaterials will be tested for their abilities to mimic natural packaging and protection strategies. This research could lead to the development of more efficient therapeutic products through a potentially general method and thus accelerate the emergence of new therapies based on bioinspired biomaterial carriers. Given the importance of molecular therapies for biomedical problems, these new biomaterials could have a significant impact on human health.
PART 2: TECHNICAL SUMMARY This proposal uses a simple synthetic motif to generate a new family of nucleic acid reactive biomaterials from readily available native ligands and polymers. This novel approach uses triazine derivatization to unify nucleic acid binding with cell-surface targeting in a multifunctional carrier design. It is the goal of this proposal to develop a general synthetic approach to transform synthetic and native biomaterials into nucleic acid carrier platforms, and elucidate the structural basis of functional intracellular delivery. This creative and original approach will yield the following expected outcomes: 1) A facile synthetic method to generate novel non-electrostatic nucleic acid binders from synthetic and biomolecular backbones; 2) a general method to transform native ligands into nucleic acid carriers; and 3) a method to target native T/U-rich nucleic acids. This research will impact targeted delivery of both RNA and DNA and enable intracellular targeting of native nucleic acid components with carriers in which binding can be decoupled from electrostatics. This decoupling allows for the fine tuning of nitrogen/phosphate (N/P) ratios geared towards uptake and release, rather than complexation. Importantly, these findings will enable the next vertical step in design of synthetic biomaterials for targeted nucleic acid chemistry delivery.
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.
