Structure-Dependent Biodistribution of Liposomal Spherical Nucleic Acids

Abstract

Spherical nucleic acids (SNAs) are a class of nanomaterials with a structure defined by a radial distribution of densely packed, short DNA or RNA sequences around a nanoparticle core. This structure allows SNAs to rapidly enter mammalian cells, protects the displayed oligonucleotides from nuclease degradation, and enables co-delivery of other drug cargoes. Here, we investigate the biodistribution of liposomal spherical nucleic acid (LSNA) conjugates, SNA architectures formed from liposome templates and DNA modified with hydrophobic end groups (tails). We compared linear DNA with two types of LSNAs that differ only by the affinity of the modified DNA sequence for the liposome template. We use single-stranded DNA (ssDNA) terminated with either a lowaffinity cholesterol tail (CHOL-LSNA) or a high-affinity diacylglycerol lipid tail (DPPE-LSNA). Both LSNA formulations, independent of DNA conjugation, reduce the inflammatory cytokine response to intravenously administered DNA. The difference in the affinity for the liposome template significantly affects DNA biodistribution. DNA from CHOL-LSNAs accumulates in greater amounts in the lungs than DNA from DPPE-LSNAs. In contrast, DNA from DPPE-LSNAs exhibits greater accumulation in the kidneys. Flow cytometry and fluorescence microscopy of tissue sections indicate that different cell populationsimmune and nonimmunesequester the DNA depending upon the chemical makeup of the LSNA. Taken together, these data suggest that the chemical structure of the LSNAs represents an opportunity to direct the biodistribution of nucleic acids to major tissues outside of the liver.

Functional Nucleic‐Acid‐Decorated Spherical Nanoparticles: Preparation Strategies and Current Applications in Cancer Therapy

“…AuNPs [71] accumulation in the lungs, whereas the DPPE-tailed liposomal SNAs exhibited high DNA trafficking to the kidneys, and both of them displayed high accumulation in the spleen. [31] The study indicates that the biodistribution of DNA-functionalized SNPs is concerned with the type of anchor, which also should be considered when designing FSNPs for targeted cancer treatment.…”

“…[55] Also, Ferrer et al directly linked DBCO-modified nonimmunogenic oligonucleotide (ODN 2138) with azide-terminated liposomes. [31]…”

The chemical biology of IL-12 productionviathe non-canonical NFkB pathway

“…The vast majority of efforts have been centered around the enhanced permeability and retention (EPR) effect and subsequent tumor cell targeting using liposomes, PLGA-PEG, albumin nanoparticles, and graft copolymers, among other formulations. [95][96][97][98][99][100][101][102][103] Targeting tumor-associated myeloid cells has also been of interest for diagnostic [104][105][106] and therapeutic effects. [107][108][109] The nanofromulations most commonly used for myeloid cell targeting include modified dextran and cyclodextrins as well as other carbohydrate-based nanomaterials.…”

A simple self-adjuvanting biomimetic nanovaccine self-assembled with the conjugate of phospholipids and nucleotides can induce a strong cancer immunotherapeutic effect

“…Generally, nanovaccine carriers are required to encapsulate and codelivery antigens and adjuvants to overcome intrinsic di culties of functional cargos and trigger delightful immune responses [4][5][6]. Recently, it has been reported that nucleic acids arranging in a dense spherical spatial form (SNAs) on a core made of gold or other polymers, can endow them unique properties, such as rapidly uptake through receptor-mediated mechanism and e cient protection against nuclease degradation [7][8][9][10]. However, the preparation of popular polymeric nanocarriers is complicated and the traditional core polymers have potential physiological toxicity [6,[11][12][13][14].…”