Compositions and methods for delivery of RNA
Inventors
Khandhar, Amit • Reed, Steven • DUTHIE, Malcolm • Erasmus, Jesse • Carter, Darrick • BERUBE, Bryan J.
Assignees
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Publication Number
US-11648321-B2
Publication Date
2023-05-16
Expiration Date
Abstract
The disclosure provides nanoemulsion compositions and methods of making and using thereof to deliver a bioactive agent such as a nucleic acid to a subject. The nanoemulsion composition comprises a hydrophobic core based on inorganic nanoparticles in a lipid nanoparticle that allows imaging as well as delivering nucleic acids. Methods of using these particles for treatment and vaccination are also provided.
Core Innovation
The invention relates to lipid-inorganic nanoemulsion nanoparticles (LIONs) for RNA delivery and immune activation, combining an imaging-capable inorganic reporter core with a cationic lipid-stabilized hydrophobic matrix. The inorganic reporter core comprises an inorganic nanoparticle, including iron oxide/iron oxides or aluminum hydroxide/oxyhydroxide, to enable imaging such as MRI.
The nanoparticles protect RNA from RNases and complex RNA to the cationic lipids to form RNA-lipid nanoparticle complexes. The system supports expression of RNA-encoded proteins/antigens in vitro and in vivo, including RNA-encoded protein/antigen examples referenced to SARS-CoV-2, Zika, and RSV as well as immunomodulating PAMP RNAs.
The documented system produces immune responses and immune activation in animals and is associated with vaccine and immune-response use cases. It reports innate immune activation, including IFN-β/IFIT2 for RIG-I/TLR3 agonist RNAs, and adaptive responses such as antibody induction.
Claims Coverage
Only one independent claim is provided in the partial content (clm-00001). The inventive features focus on RNA encoding of an RNA polymerase complex region plus a protein antigen, administration to generate an immune response, and lipid nanoparticle physical properties and composition, including cationic lipid surface and a hydrophobic liquid-phase oil core with RNA complexed to cationic lipids, along with a specified z-average diameter range measured by dynamic light scattering.
Administering RNA and protein antigen to generate an immune response
Administering to a subject a composition comprising RNA molecules, wherein the RNA molecules comprise a sequence encoding for an RNA polymerase complex region from an RNA virus genome and a protein antigen.
Lipid nanoparticles with a specified z-average diameter by dynamic light scattering
Administering lipid nanoparticles characterized as having a z-average diameter particle size measurement of 20 nm to 80 nm when measured using dynamic light scattering.
Cationic lipid surface and hydrophobic core with liquid oil in liquid phase at 25°C
The lipid nanoparticles comprise a surface comprising cationic lipids and a hydrophobic core, wherein the hydrophobic core comprises liquid oil, and wherein lipids present in the hydrophobic core are in liquid phase at 25 degrees Celsius.
RNA complexed to cationic lipids to form RNA-lipid nanoparticle complexes
Complexing the RNA molecules to the cationic lipids to form RNA-lipid nanoparticle complexes.
The claim coverage centers on generating an immune response by administering a composition containing RNA encoding an RNA polymerase complex region from an RNA virus genome together with a protein antigen, formulated in cationic-lipid-containing lipid nanoparticles having a specified 20 nm to 80 nm z-average diameter (DLS). The lipid nanoparticles additionally include a hydrophobic core comprising liquid oil with lipids in liquid phase at 25°C, with RNA complexed to cationic lipids to form RNA-lipid nanoparticle complexes.
Stated Advantages
Protects RNA from RNases.
Enables expression of RNA-encoded proteins/antigens in vitro and in vivo.
Supports imaging capability via an inorganic reporter core for MRI contrast.
Produces enhanced immune responses compared to an NLC control.
Induces antibody responses in animals.
Activates innate immune pathways, including IFN-β/IFIT2 for RIG-I/TLR3 agonist RNAs.
Enables prolonged secreted protein expression in mice.
Documented Applications
Vaccine and immune-response use cases, including RNA encoding an antigen and immune activation in a subject.
RNA-encoded protein/antigen expression and immune responses associated with SARS-CoV-2, Zika, and RSV examples referenced in the document.
Immunomodulating PAMP RNAs, including RIG-I agonist RNAs and TLR3 agonist RNAs, with innate immune activation (IFN-β/IFIT2) and related outcomes.
Imaging-related use, including MRI contrast based on changes in T1/T2 relaxivities associated with the inorganic reporter core.
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