Structure-Dependent Biodistribution of Liposomal Spherical Nucleic Acids

Area of Science:

• Nanotechnology
• Biomedical Engineering
• Molecular Biology

Background:

• Spherical nucleic acids (SNAs) are nanomaterials with DNA/RNA radially arranged on a core.
• SNAs facilitate cellular entry, resist degradation, and enable co-delivery of therapeutics.
• Liposomal spherical nucleic acid (LSNA) conjugates represent a novel SNA architecture.

Purpose of the Study:

• To investigate the biodistribution of LSNA conjugates with varying DNA-lipid tail affinities.
• To compare the accumulation of LSNA-DNA in different tissues and cell types.
• To assess the impact of LSNA structure on inflammatory responses to DNA.

Main Methods:

• Comparison of linear DNA with two LSNA formulations: low-affinity cholesterol-tailed (CHOL-LSNA) and high-affinity diacylglycerol-tailed (DPPE-LSNA).
• Intravenous administration of LSNA formulations in vivo.
• Biodistribution analysis using flow cytometry and fluorescence microscopy of tissue sections.
• Assessment of inflammatory cytokine response.

Main Results:

• Both LSNA formulations reduced inflammatory cytokine responses to intravenously administered DNA.
• DNA biodistribution was significantly affected by the DNA-lipid tail affinity.
• CHOL-LSNAs showed greater lung accumulation, while DPPE-LSNAs accumulated more in the kidneys.
• LSNA chemical structure influenced sequestration by immune and non-immune cells.

Conclusions:

• LSNA chemical structure offers a strategy to control nucleic acid biodistribution.
• Nucleic acid delivery can be directed to specific tissues outside the liver by tailoring LSNA design.
• LSNAs demonstrate potential for targeted delivery of nucleic acid-based therapeutics.