Document text
Principal Investigator: Connie Wu
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $371,606
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY: RNA therapeutics are experiencing a renaissance with the clinical successes of the
COVID-19 messenger RNA (mRNA) vaccines. In parallel, nanomaterials have emerged as highly promising
vehicles for RNA delivery. However, despite considerable scientific advances in nanoparticle therapeutics over
the last several decades, few nanoparticle-based RNA therapeutics have been clinically approved. As the RNA
therapeutics landscape expands, there remain key understanding gaps that must be addressed to inform the
rational design of RNA therapeutic systems across molecular, cellular, and organismal levels and enable
broad clinical translation: (1) how RNA cargo parameters, carrier properties, and their combinations govern
functional in vivo RNA delivery; (2) how the biological environment of the host alters RNA nanocarriers and their
in vivo functionalities; and (3) in turn, how RNA therapeutic systems modify the host. Further exacerbating these
knowledge gaps is a lack of high-sensitivity, high-throughput tools for interrogation of functional in vivo RNA
delivery, nanoparticle-biomolecule interactions, and the host response. The proposed program will adopt multi-
pronged strategies to address these challenges, by integrating our complementary expertise in ultrasensitive
biomolecule detection, RNA engineering, and nanoparticle drug delivery. Using mRNA as a representative RNA
drug, we seek to elucidate design rules for both RNA nanocarrier and cargo for functional RNA delivery.
Leveraging our technology for multiplexed single-molecule detection of low abundance biomolecules, we will
pursue orthogonal focus areas: (1) develop and apply an ultrasensitive screening platform for pooled in vivo
analysis of mRNA therapeutic systems, to identify RNA cargo and carrier determinants of functional mRNA
delivery; (2) understand and predict the host response to RNA therapeutic systems via high-multiplex single-
molecule protein detection; and (3) probe the biomolecular interactions of nanocarriers and their effects on in
vivo functionality via high-throughput, high-resolution profiling of biomolecule adsorption. These three
independent yet synergistic directions align well with NIGMS mission objectives in the application of innovative
physical methodologies and quantitative approaches to establish foundations for disease treatment. If successful,
this program will build an integrated understanding of RNA therapeutic system design rules and host factors that
govern RNA delivery and individual response. The ultrasensitive profiling tools developed in this work will be of
broad utility across diverse RNA therapeutic systems and disease applications.
Terms: <Address><Adopted><Adsorption><Area><Biological><COVID-19><CV-19><Clinical><Coronavirus Infectious Disease 2019><Detection><Dimensions><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drugs><Engineering><Environment><Foundations><Functional RNA><Host Factor><Host Factor Protein><Immune response><Immunological response><In vivo analysis><Integration Host Factors><Knowledge><Medication><Messenger RNA><Methodology><Mission><Molecular><NIGMS><National Institute of General Medical Sciences><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Pharmaceutical Preparations><Property><Proteins><RNA><RNA Gene Products><RNA based therapeutics><RNA based therapy><RNA delivery><RNA therapy><RNA vaccine><RNA-based vaccine><Renaissance><Resolution><Ribonucleic Acid><Scientific Advances and Accomplishments><System><Technology><Untranslated RNA><Work><biologic><clinical translation><clinically translatable><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><drug/agent><experience><host response><immune system response><immunoresponse><improved><in vivo><in vivo evaluation><in vivo testing><individual response><individualized response><innovate><innovation><innovative><mRNA><mRNA delivery><mRNA vaccine><mRNA-based vaccine><messenger RNA delivery><nano particle><nano-sized particle><nanocarrier><nanomaterials><nanoparticle><nanoparticle drug><nanoparticle therapy><nanosized particle><nanovessel><noncoding><programs><rational design><resolutions><scientific accomplishments><scientific advances><screening><screenings><single molecule><success><therapeutic RNA><therapeutic nanoparticles><tool>