Disulfide-Containing Molecular Sticker Assists Cellular Delivery of DNA Nanoassemblies by Bypassing Endocytosis

Abstract

The delivery efficiency of DNA nanoassemblies to the cytosol remains unsatisfactory due to endoand lysosomal entrapment and degradation, which restricts their bioanalytical and biomedical applications. Herein, the authors developed a disulfide-containing molecular sticker (DSMS) assisted approach to achieve efficient cytosolic delivery of DNA nanoassemblies. DSMS is designed to consist of a disulfide unit for thiol-mediated uptake and a guanidinium cation unit for strongly adhering to DNA nanoassemblies. After attaching with DSMS, a set of DNA nanoassemblies maintained their original three-dimensional features but had a different cellular internalization pathway. These results demonstrated that DSMS-DNA nanoassemblies complex did not enter the cells via endocytosis but instead entered through thiol-mediated direct uptake. Taking advantages of this facile assembly, universal applicability, and direct cytosolic delivery, DSMS might serve as a potent agent to facilitate the applications of DNA nanoassemblies in a variety of fields, such as bioimaging, drug delivery, and gene therapy.

Poly(disulfide)s: From Synthesis to Drug Delivery

“…Recently, a similar salt bridge strategy was further exploited for the delivery of DNA. 149 Ping et al recently reported a series of CPDs by exploring mechanisms to universally deliver different forms of CRISPR-Cas9 components, including Cas9 plasmid, sgRNA, Cas9 mRNA, and Cas9 ribonucleoprotein (RNP). After screening, DET-CPD-12 with diethylenetriamine (DET) and CPD blocks was utilized for in vivo delivery of CRISPR-Cas9 targeting CCNE1 to successfully prevent fulminant hepatic failure (FHF).…”

Disulfide Bridging Strategies in Viral and Nonviral Platforms for Nucleic Acid Delivery

“…The assembly and disassembly processes were controlled by the addition of peroxide and GSH, respectively, which could be used as a stimulus-responsive cargo delivery system. Creation of a disulfide-containing molecular sticker (DSMS) on a DNA nanostructure was reported to aid in cellular uptake . DSMS was attached to the DNA nanostructures through salt bridges formed by the cationic guanidinium groups, and the disulfide-containing tail helped in direct delivery to cells.…”

“…Creation of a disulfide-containing molecular sticker (DSMS) on a DNA nanostructure was reported to aid in cellular uptake. 211 DSMS was attached to the DNA nanostructures through salt bridges formed by the cationic guanidinium groups, and the disulfide-containing tail helped in direct delivery to cells.…”

Regulation of Biological Functions at the Cell Interface by DNA Nanostructures

“…Besides the abovementioned surface modification by peptides, a disulfide-containing molecular sticker (DSMS) was reported to be utilized to assist the cellular delivery of DNA nanostructures. [41] Consisted of guanidinium cation units, DSMS can strongly adhere to phosphate groups of DNA structures via multiple salt bridges. The characterization results showed that the [29] Copyright 2020, Nature Publishing Group.…”