Noncoding ribonucleic acid molecules called microRNAs (miRNAs) have recently emerged as important biological regulators that suppress the expression of target genes via messenger RNA degradation or translationalrepression.SincemiRNAscanregulategeneexpression,thereisintenseinterestinutilizingthese molecules as tools to halt disease progression. Unfortunately, naked miRNAs are not suitable for clinical use due to their poor stability, limited circulation half-??life, and inability to enter cells. Accordingly, researchers have begun to incorporate miRNAs into nanocarriers to facilitate their in vivo delivery. While some progress has been made, there is substantial room for improvement, evidenced by the fact that only a single miRNA nanocarrier has entered clinical trials. This lack of clinical translation indicates there is an urgent need for mechanistic studies to elucidate the underlying principles that dictate the interactions between miRNA nanocarriers and biological systems.
We aim to address this need by capitalizing on our unique expertise in nanoparticle design, which includes experience with both miRNA nanocarriers and targeted nanoparticle systems.Morespecifically,wewillelucidatehowthephysicalandchemicalpropertiesofmiRNAnanocarriers influence five specific outcomes related to the challenges associated with in vivo miRNA delivery. These include: stability and nuclease resistance, cell uptake and intracellular trafficking, gene regulation potency, biodistribution, and ability to halt progression of diseases including breast cancer and osteoporosis. By studying these five outcomes, we can increase understanding of the effects of miRNA nanocarriers on the body,aswellastheeffectsofthebodyonmiRNAnanocarriers.Thiswillenableustoestablishasetofdesign rules that govern the interactions between miRNA nanocarriers and biological systems and which can be applied in the denovo synthesis of miRNA nanocarriers to maximize their site-??specific delivery and efficacy. Over the next five years we will focus explicitly on studying how incorporating targeting agents into miRNA nanocarriers influences the five aforementioned outcomes. By comparing different types of targeting agents (e.g.,antibodies or proteins) we can increase knowledge of the mechanisms of nanoparticle interactions with cell surface receptors and the impact they have on signal transduction. We hypothesize that targeting agents can not only promote cell binding, but also manipulate signaling cascades via receptor-??mediated processes. If this hypothesis is correct, combining miRNA delivery with targeting agent-??mediated signal cascade manipulation may have synergistic effects on diseased cells. Importantly, in the future we will expand our studiestoinvestigateotherfeaturesofmiRNAnanocarrierssuchassize,shape,andstiffness.Thiswillenable ustodistinguishhowthenanocarrieritselfinfluencesvariousbiologicaloutcomes.Thisimportantinformation willenablecreationofaccuratedesignrulesthatwillfacilitatemoreefficientclinicaltranslationofnewmiRNA nanocarriersfordiseaseintervention.

Public Health Relevance

MicroRNAs (miRNAs) are promising tools for gene regulation, but their successful application requires the use of nanocarriers; thus, there is an urgent need for fundamental studies to elucidate the underlying principles that dictate the interactions between miRNA nanocarriers and biological systems. Using models of breast cancer and osteoporosis, we will apply our expertise in nanoparticle design to investigate how the physical and chemical properties of miRNA nanocarriers influence their stability, cell and tissue uptake, and ability to regulate gene expression. By establishing design rules regarding the application of miRNA nanocarriers, we aim to facilitate their efficient clinical translation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
3R35GM119659-03S1
Application #
9699092
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Okita, Richard T
Project Start
2016-08-01
Project End
2021-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Delaware
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Goyal, Ritu; Kapadia, Chintan H; Melamed, Jilian R et al. (2018) Layer-by-layer assembled gold nanoshells for the intracellular delivery of miR-34a. Cell Mol Bioeng 11:383-396
Melamed, Jilian R; Kreuzberger, Nicole L; Goyal, Ritu et al. (2018) Spherical Nucleic Acid Architecture Can Improve the Efficacy of Polycation-Mediated siRNA Delivery. Mol Ther Nucleic Acids 12:207-219
Riley, Rachel S; Day, Emily S (2017) Gold nanoparticle-mediated photothermal therapy: applications and opportunities for multimodal cancer treatment. Wiley Interdiscip Rev Nanomed Nanobiotechnol 9:
Riley, Rachel S; Day, Emily S (2017) Frizzled7 Antibody-Functionalized Nanoshells Enable Multivalent Binding for Wnt Signaling Inhibition in Triple Negative Breast Cancer Cells. Small 13:
Billingsley, Margaret M; Riley, Rachel S; Day, Emily S (2017) Antibody-nanoparticle conjugates to enhance the sensitivity of ELISA-based detection methods. PLoS One 12:e0177592
Melamed, Jilian R; Riley, Rachel S; Valcourt, Danielle M et al. (2016) Using Gold Nanoparticles To Disrupt the Tumor Microenvironment: An Emerging Therapeutic Strategy. ACS Nano 10:10631-10635