Spherical nucleic acid-based constructs as immunostimulatory agents for prophylactic and therapeutic use
Aspects of the invention relate to spherical nucleic acid-based constructs and related methods and compositions thereof. The compositions of the invention are useful for activating agonists of nucleic acid interacting complexes, such as TLRs, stimulating an immune response, and treating diseases such as infectious disease, cancer, allergies, allergic diseases, and autoimmune disease.
1. A nanoscale construct, comprising
a corona comprised of an exterior shell composed of nucleic acid molecules arranged in a geometrical position around a nanoparticle core, wherein the nucleic acid molecules are CpG oligonucleotides, wherein the nucleic acid molecules contain a spacer which comprises an oligoethylene and do not comprise an oligonucleotide spacer, and wherein the diameter of the nanoparticle core is about 1 nm to about 40 nm.
2. The nanoscale construct of claim 1 , wherein the nucleic acid molecules have a surface density of at least 0.3 pmol/cm 2 .
3. The nanoscale construct of claim 1 , wherein the nanoparticle core at the center of the corona is not metallic.
4. The nanoscale construct of claim 1 , wherein the spacer is an oligoethylene.
5. The nanoscale construct of claim 1 , wherein the nanoparticle core at the center of the corona is hollow.
6. The nanoscale construct of claim 1 , wherein the nanoparticle core is degradable.
7. The nanoscale construct of claim 1 , wherein the CpG oligonucleotides have a phosphorothioate (PS) backbone.
8. The nanoscale construct of claim 1 , further comprising a cancer antigen.
9. The nanoscale construct of claim 1 , wherein the diameter of the nanoparticle core is about 10 nm to about 30 nm.
10. The nanoscale construct of claim 1 , wherein the CpG oligonucleotides comprise the sequence of SEQ ID NO: 30.
11. The nanoscale construct of claim 1 , wherein the CpG oligonucleotides are linked to the nanoparticle core through a linker at the 3′-end.
12. The nanoscale construct of claim 1 , wherein the CpG oligonucleotides are between 8 and 50 nucleotides in length.
13. The nanoscale construct of claim 1 , wherein the CpG oligonucleotides are between 8 and 30 nucleotides in length.
14. The nanoscale construct of claim 4 , wherein the oligoethylene is hexaethylene glycol.
15. The nanoscale construct of claim 1 , wherein the nucleic acid molecules arranged in a geometrical position form a spherical shape around the nanoparticle core.
16. The nanoscale construct of claim 1 , wherein the nucleic acid molecules are linked directly to the nanoparticle core.
17. The nanoscale construct of claim 2 , wherein the surface density is no greater than about 35-40 pmol/cm 2 .
18. The nanoscale construct of claim 1 , wherein the CpG oligonucleotides are 6 to 100 nucleotides in length.
19. The nanoscale construct of claim 1 , wherein the nucleic acid molecules are linked to other nucleic acid molecules through a non-covalent linkage.
20. The nanoscale construct of claim 1 , wherein the CpG oligonucleotides have at least one phosphodiester internucleotide linkage.