Compositions and methods for delivery of RNA
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.
1. A nanoemulsion composition comprising a plurality of nanoemulsion particles, wherein the plurality of nanoemulsion particles comprise:
a hydrophobic core comprising a mixture of a liquid oil and a solid inorganic nanoparticle;
a cationic lipid;
a hydrophilic surfactant;
a hydrophobic surfactant; and
a nucleic acid, wherein the nucleic acid modulates innate immune response and is complexed with the nanoemulsion particles.
2. The nanoemulsion composition of claim 1 , wherein the nucleic acid is RNA.
3. The nanoemulsion composition of claim 2 , wherein the RNA s double-stranded RNA.
4. The nanoemulsion composition of claim 1 , wherein the nucleic acid is DNA.
5. The nanoemulsion composition of claim 1 , wherein the nucleic acid is a TLR agonist.
6. The nanoemulsion composition of claim 5 , wherein the TLR agonist is a TLR3 agonist.
7. The nanoemulsion composition of claim 1 , wherein the nucleic acid is a RIG-I agonist.
8. The nanoemulsion composition of claim 1 , wherein the hydrophobic surfactant is selected from the group consisting of sorbitan monostearate, sorbitan monooleate, and sorbitan trioleate.
9. The nanoemulsion composition of claim 1 , wherein cationic lipid is selected from the group consisting of 1,2-dioleoyloxy-3-(trimethylammonium)propane (DOTAP); 3b-[N-(N′,N-dimethylaminoethane)-carbamoyl]cholesterol (DC Cholesterol); dimethyldioctadecylammonium (DDA); 1,2-dimyristoyl-3-trimethylammoniumpropane (DMTAP); dipalmitoyl(C16:0)trimethyl ammonium propane (DPTAP); distearoyltrimethylammonium propane (DSTAP); N-[l-(2,3- dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA); N,N-dioleoyl-N,N-dimethylammonium chloride (DODAC); 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (DOEPC);1,2-dioleoyl-3-dimethylammonium-propane (DODAP); and 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA); and 1, r-((2-(4-(2-((2-(bis(2-hydroxydodecyl)amino)ethyl) (2-hydroxydodecyl)amino)ethyl)piperazin-l-yl)ethyl)azanediyl)bis(dodecan-2-ol) (C 12-200).
10. The nanoemulsion composition of claim 9 , wherein the cationic lipid is DOTAP.
11. The nanoemulsion composition of claim 1 , wherein the solid inorganic nanoparticle is selected from the group consisting of metal salts, metal oxides, metal hydroxides, and metal phosphates.
12. The nanoemulsion composition of claim 1 , wherein the solid inorganic nanoparticle comprises iron oxide.
13. The nanoemulsion composition of claim 12 , wherein the iron oxide is magnetite (Fe 3 O 4 ), maghemite (y-Fe 2 O 3 ), wustite (FeO), hematite (a-Fe 2 O 3 ), or any combination thereof.
14. The nanoemulsion composition of claim 1 , wherein the liquid oil is a vegetable oil, an animal oil or a synthetically prepared oil.
15. The nanoemulsion composition of claim 1 , wherein the liquid oil is capric/caprylic triglyceride, vitamin E, lauroyl polyoxylglyceride, monoacylglycerol, squalene, or any combination thereof.
16. The nanoemulsion composition of claim 1 , wherein the liquid oil is squalene, sunflower oil, soybean oil, olive oil, grapeseed oil, capric/caprylic triglyceride, or any combination thereof.
17. The nanoemulsion composition of claim 1 , wherein the liquid oil is squalene.
18. The nanoemulsion composition of claim 1 , wherein the hydrophilic surfactant comprises polyethylene oxide.
19. The nanoemulsion composition of claim 18 , wherein the polyethylene oxide comprises polyoxyethylene sorbitan ester.
20. The nanoemulsion composition of claim 1 , wherein the hydrophilic surfactant comprises polysorbate.
21. The nanoemulsion composition of claim 20 , wherein the polysorbate comprises polysorbate 80.
22. The nanoemulsion composition of claim 1 , wherein the solid inorganic nanoparticle has an average diameter from about 3 nm to about 50 nm.
23. The nanoemulsion composition of claim 1 , wherein the nanoparticles comprise an average diameter from about 40 nm to about 200 nm, wherein the average diameter is a z-average hydrodynamic diameter measured by dynamic light scattering.
24. The nanoemulsion composition of claim 1 , wherein the nanoparticles comprise an average diameter from about 40 nm to about 80 nm, wherein the average diameter is a z-average hydrodynamic diameter measured by dynamic light scattering.
25. The nanoemulsion composition of claim 1 , wherein the liquid oil comprises squalene, wherein the solid inorganic nanoparticle comprises iron oxide, wherein the cationic lipid comprises DOTAP, wherein the hydrophobic surfactant comprises sorbitan monostearate, and wherein the hydrophilic surfactant comprises polysorbate 80.
26. The nanoemulsion composition of claim 1 , wherein the liquid oil is squalene, wherein the solid inorganic nanoparticle is iron oxide, wherein the cationic lipid is DOTAP, wherein the hydrophobic surfactant is sorbitan monostearate, and wherein the hydrophilic surfactant is polysorbate 80.
27. The nanoemulsion composition of claim 26 , wherein the composition further comprises sodium citrate.
28. The nanoemulsion composition of claim 1 , wherein the liquid oil comprises from about 2% to about 40% w/v squalene, wherein the solid inorganic nanoparticle comprises from about 0.001% to about 10% w/v iron oxide, wherein the cationic lipid comprises from about 0.2% to about 10% w/v DOTAP, wherein the hydrophobic surfactant comprises from about 0.25% to about 5% w/v sorbitan monostearate, and wherein the hydrophilic surfactant comprises from about 0.5% to about 10% w/v polysorbate 80.