CAREER: Developing albumin-binding responsive polypeptides for nucleic acid delivery

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PART 1: NON-TECHNICAL SUMMARYNucleic acid-based drugs have been identified as an effective treatment for various diseases including cancer, viral infections, and genetic disorders. This was highlighted by the use of messenger RNA (mRNA) vaccines during the Covid-19 pandemic. Due to the intrinsic physicochemical properties of nucleic acids, including negative charges, high hydrophilicity, and susceptibility to enzymatic degradation positively charged delivery carriers are typically required to successfully exert their functions. However, most of the current carriers suffer from unsatisfactory toxicities and low delivery efficiencies. This limits the widespread use of nucleic acid therapeutics in a clinical setting. This CAREER project proposes innovative approaches to developing biologically friendly, safe, and effective nucleic acid delivery carriers. These polypeptide-based carriers are less toxic and can effectively deliver nucleic acids to diseased sites. The structure of the polypeptide will be systematically investigated for optimized efficacy. Protein-binding molecules will also be used to further reduce the carrier’s toxicity along with an increase in delivery efficiency. This project provides critical insights into the development of biomaterials for nucleic acid delivery and many other biomedical applications in disease treatment. Integrated with the research effort, the principal investigator proposes a series of educational projects to help K-12 students understand chemistry and science. This program aims to train graduate and undergraduate students, particularly women and underrepresented minorities, in the field of biomaterials, and ultimately contribute to the development of the next-generation STEM workforce.PART 2: TECHNICAL SUMMARYThis CAREER project aims to develop safe and effective polymeric delivery carriers for nucleic acid therapeutics, including small interfering RNA (siRNA) and messenger RNA (mRNA). siRNA and mRNA are a class of “information drugs” with far-reaching therapeutic potential and have been investigated for the treatment of various diseases, including cancers, viral infections, and genetic and metabolic disorders. However, broad clinical adoption of nucleic acid therapeutics has been challenged by the fact that nucleic acids are unstable and cannot efficiently cross cell membranes besides being immunogenic. To tackle the challenges of nucleic acid therapeutics for clinical adoption, this project is dedicated to the development of albumin-binding responsive polypeptides that have minimal toxicity. Therefore, these polypeptides can carry, protect, deliver, and release nucleic acid into target tissues and cells, with an emphasis on the delivery process. This will be accomplished through two innovative approaches to reduce toxicity and improve the effectiveness of nucleic acid therapeutics: 1) development of redox-responsive polypeptides, wherein pendant cationic amines are connected via disulfide bonds to polypeptide backbones; 2) conjugation of the albumin-binding molecule Evans Blue to polypeptides (EBylation) to hitchhike endogenous albumin for shielding and camouflaging the positive charge for minimal cytotoxicity and immunotoxicity. This project seeks to systematically investigate the structure-property relationship between responsive amine moieties and nucleic acid delivery efficiency. Additionally, the effect of EBylation on nucleic acid binding, cellular uptake, and transfection will be studied. The concept of reversible protein binding will also be introduced to camouflage the self-assembled materials for enhancement of biocompatibility and reduction of undesirable interactions. This proposal will help prepare a diverse group of undergraduate and graduate students to tackle social challenges and complex scientific problems. It will be complemented with outreach activities and efforts for students in K-12, ultimately contributing to the development of the next-generation STEM workforce.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.