Document text
Principal Investigator: Jilian R Melamed
Organization: CARNEGIE-MELLON UNIVERSITY
Fiscal Year: 2021
Award: $66,390
Funding agency: National Institute of Biomedical Imaging and Bioengineering
While gene therapy with mRNA offers tremendous potential to transform the management of genetic
diseases, delivering mRNA outside the reticuloendothelial system (e.g. liver and spleen) remains challenging.
Without carriers that can reach organs such as the lungs, heart, brain, or pancreas, the potential of mRNA to
treat diseases of those organs, such as asthma, coronary artery disease, multiple sclerosis, and diabetes, will
remain untapped. This research will establish the protein corona as a new lipid nanoparticle design element that
can be engineered to achieve mRNA delivery outside the reticuloendothelial system. Upon injection into the
body, lipid nanoparticles are immediately coated in local proteins, forming a protein corona that interfaces with
cells and tissues. The composition of that natural corona has been shown to strongly influence nanoparticle fate
in vivo. This work will develop “smart” protein coronas by pre-coating mRNA lipid nanoparticles with proteins that
localize to organs outside the reticuloendothelial system prior to administration.
In Aim 1, a small library of naturally-occurring proteins will be evaluated for their ability to direct mRNA
delivery to non-reticuloendothelial organs, including the lungs, heart, brain, and pancreas, in C57BL/6 mice.
Imaging and flow cytometry will be used to identify organ and cellular targets of smart corona-coated mRNA lipid
nanoparticles. Aim 2 will elucidate the mechanisms by which smart corona-coated lipid nanoparticles enable
differential organ targeting. Smart coronas may enable differential targeting by altering circulation time, by
recruiting additional serum proteins that serve as active targeting agents, or by binding specific cell surface
receptors via the smart corona itself or via additionally adsorbed proteins. Proteomic analysis will determine what
proteins adsorb coated-lipid nanoparticles upon intravenous injection, and cell receptor blocking studies will
identify cellular targets that facilitate effective mRNA delivery.
This work is innovative in that it will establish the protein corona as a previously-unappreciated
nanoparticle design element that can be engineered to enable mRNA delivery to challenging organ targets. While
efficacious smart coronas will provide researchers with new tools to advance drug targeting, mechanistic insights
will inform future smart corona design. This research is significant because it will contribute a paradigm-shifting
targeting strategy to accelerate the clinical translation of mRNA therapeutics for extrahepatocellular diseases.
Further, the results obtained by this research will advance the delivery of nucleic acids, small molecules, and
proteins from diverse drug carriers, such nanoparticles, drug conjugates, and implantable devices. Ultimately,
the knowledge generated by this work has the potential to transform and accelerate the development of targeted
drug carriers.
Terms: <Apo-E><ApoE><Apolipoprotein E><Asthma><Binding><Biodistribution><Blood Circulation><Blood Serum><Bloodstream><Body Tissues><Brain><Brain Nervous System><Bronchial Asthma><C57BL/6 Mouse><Carrier Proteins><Cell Body><Cell Surface Receptors><Cells><Chemistry><Circulation><Clinical><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Cytoplasm><DNA Therapy><Data><Development><Diabetes Mellitus><Disease><Disorder><Disseminated Sclerosis><Drug Carriers><Drug Kinetics><Drug Targeting><Drugs><Elements><Encephalon><Engineering><FDA approved><Face><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><Gene Transfer Clinical><Genes><Genetic Diseases><Genetic Intervention><Genetic Translation><Heart><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatocyte><IVIS SpectrumCT><IVIS imaging><IVIS optical imaging><IVIS spectral imaging><IVIS spectrum><IVIS system><Image Cytometry><Immune><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunotherapy><Injections><Investigators><Knowledge><Libraries><Library Materials><Lipid Trafficking><Liver><Liver Cells><Liver diseases><Luciferase Immunologic><Luciferases><Lung><Lung Respiratory System><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Medication><Messenger RNA><Mice><Mice Mammals><Molecular><Molecular Interaction><Multiple Sclerosis><Murine><Mus><Organ><Pancreas><Pancreatic><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Production><Property><Protein Engineering><Protein Replacement Therapy><Proteins><Proteomics><RNA delivery><Receptor Cell><Receptor Protein><Research><Research Personnel><Researchers><Reticuloendothelial System><Scientific Advances and Accomplishments><Serum><Serum Proteins><Short interfering RNA><Small Interfering RNA><Spleen><Spleen Reticuloendothelial System><Therapeutic><Time><Tissues><Translating><Transport Protein Gene><Transport Proteins><Transporter Protein><Work><atherosclerotic coronary disease><biomedical implant><cellular targeting><clinical translation><coronary arterial disease><design><designing><develop a vaccine><development of a vaccine><developmental><diabetes><drug/agent><efficacy study><enzyme replacement therapy><faces><facial><flow cytophotometry><gene therapy><gene-based therapy><genetic condition><genetic disorder><genetic protein engineering><genetic therapy><genomic therapy><hepatic body system><hepatic disease><hepatic organ system><hepatopathy><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><implant device><implantable device><improved><in vivo><in vivo imaging system><indwelling device><innovate><innovation><innovative><insight><insular sclerosis><intravenous injection><lipid nanoparticle><lipid transport><liver disorder><mRNA><mRNA Translation><mRNA delivery><mRNA tagging><nano><nano carrier><nano particle><nano particle delivery><nano particle drug><nano-sized particle><nanocarrier><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanoparticle drug><nanosized particle><nucleic acid delivery><protein design><pulmonary><receptor><recruit><scientific accomplishments><scientific advances><siRNA><small molecule><success><targeted agent><tool><vaccine development><vaccine formulation>