Lipid Nanoparticle Spherical Nucleic Acids for Intracellular DNA and RNA Delivery

Abstract

Lipid nanoparticle SNAs (LNP-SNAs) have been synthesized for the delivery of DNA and RNA to targets in the cytoplasm of cells. Both the composition of the LNP core and surface-presented DNA sequences contribute to LNP-SNA activity. G-rich sequences enhance the activity of LNP-SNAs compared to Trich sequences. In the LNP core, increased cholesterol content leads to greater activity. Optimized LNP-SNA candidates reduce the siRNA concentration required to silence mRNA by 2 orders of magnitude compared to liposome-based SNAs. In addition, the LNP-SNA architectures alter biodistribution and efficacy profiles in mice. For example, mRNA within LNP-SNAs injected intravenously is primarily expressed in the spleen, while mRNA encapsulated by LNPs (no DNA on the surface) was expressed primarily in the liver with a relatively small amount in the spleen. These data show that the activity and biodistribution of LNP-SNA architectures are different from those of conventional liposomal SNAs and therefore potentially can be used to target tissues.

Nucleic Acids and Their Analogues for Biomedical Applications

“…The GNC-siRNA efficiently downregulated the NGF expression in Panc-1 cells, pancreatic tumors, and further inhibited the tumor progression in three pancreatic tumor models. Most recently, Sinegra and coworkers synthesized the lipid nanoparticle spherical nucleic acids (LNP-SNAs) for the delivery of DNA and RNA into the cell cytoplasm ( Figure 3 b) [ 47 ]. A library of LNP-SNAs were synthesized via the ethanol dilution approach by mixing DNAs or RNAs in aqueous solution with different lipids including an ionizable lipid, phospholipid, lipid-PEG, and cholesterol in ethanol.…”

“…( a ) Schematic illumination of allosteric ribozymes for detection of TPP in whole blood. Reprinted with permission from [ 47 ]. Copyright 2021, American Chemical Society.…”

Engineering Macrophages via Nanotechnology and Genetic Manipulation for Cancer Therapy

“…These NPs were mainly phagocytosed by macrophages residing in the liver and spleen after tail vein injection, leading to a gene-editing efficiency of greater than 8% in macrophages ( 183 ). Nanotechnology can also be used to transport mRNA or siRNA to a specific cell population in a targeted manner ( 184 , 185 ). For example, NPs carrying PTEN mRNA were effectively delivered to PTEN null cancer cells, and restoration of PTEN expression induced immunogenic death of cancer cells and thus induced potent antitumor immune responses in melanoma tumor-bearing mice ( 186 ).…”

DNA Nanodevice-Based Drug Delivery Systems

“…The results undoubtedly suggest that people can only use the payload itself to achieve gene and drug targeting without necessarily requiring other carrier systems. Differing from the drug core, Sinegra et al [ 90 ] synthesized lipid-core lipid nanoparticles SNA(LNP-SNA) for the delivery of DNA and RNA to targeted sites in the cytoplasm. Its surface DNA accumulation, G sequence enrichment, and core lipid content increase can all lead to the enhancement of LNP-SNA activity.…”

“… Different spherical nucleic acid (SNA) structures for drug targeted delivery. ( a ) SNA-based ASO-drug conjugates exert anti-melanoma effects as the skin depigmentation agent, reproduced with permission from Reference [ 88 ], Copyright 2021 American Chemical Society; ( b ) optimization of the composition of the lipid nanoparticle SNA (LNP-SNA) and changes in the biodistribution and therapeutic properties of the structure in mice compared to conventional LNP, reproduced with permission from Reference [ 90 ], Copyright 2021 American Chemical Society. …”