Virus-Inspired Approach to Nonviral Gene Delivery Vehicles

Abstract

The basic TAT peptide, responsible for translocation of the HIV-TAT protein, has been conjugated to a variety of artificial nanoscopic materials to transport them across the cellular membrane. However, attempts to translocate genes using the TAT-peptide had met with limited success. We hypothesized that the cationic nature of the peptide does not allow for displaying these peptides on the surface of the polyplex. To circumvent this potential issue, we have developed a new molecular design strategy where the TAT-peptide can be effectively displayed on the surface of the polyplex, thus enhancing gene expression.

Polymer nanogels: A versatile nanoscopic drug delivery platform

“…This often requires the design of a delivery vehicle to allow for attachment of active targeting ligands after assembly of the drug carrier. The importance of this strategy was demonstrated in a DNA delivery system where the sequence of attachment of a cell penetrating peptide made significant differences on DNA delivery efficiency [35] (see Figure 12 and 13). It was observed that if the TAT peptide was attached to the delivery vehicle before complexation with DNA, the delivery transfection efficiency was 25% lower than when TAT was attached to the preformed assembly.…”

Invading target cells: multifunctional polymer conjugates as therapeutic nucleic acid carriers

“…They combined PLL as a nucleic acid packaging module, PLL-modified transferrin or a synthetic trigalactose ligand as a TfR or asialoglycoprotein receptor binding module and PLL-bound influenza peptides as endosomolytic modules to form an "artificial virus", which was then used for the delivery of nucleic acids [118,119]. HIV derived TAT peptide, a basic sequence of 10 amino acids (GRKKRRQRRR) within the transactivator of transcription (TAT) protein has been utilized for nucleic acid delivery [120][121][122]. However Roy et al hypothesized that the cationic nature of the TAT peptide hinders exposition on the polyplex surface.…”

“…However Roy et al hypothesized that the cationic nature of the TAT peptide hinders exposition on the polyplex surface. They showed, that the length of PEG linkers between the cationic polymer backbone and the TAT peptide influences its availability and thus transfection efficiency [120].…”

“…anhydrides, N-hydroxysuccinimide (NHS) esters or carboxylic groups activated with carbodiimides) to form amide bonds. Roy et al used maleimide-PEG-NHS, a heterobifunctional linker with amine-and thiole-reactive termini, for the conjugation of cell-penetrating TAT peptides to PEI [120]. Fella et al reported the synthesis of an amine-reactive PEGylation reagent for pH-reversible PEI polyplex shielding [65].…”

Virus‐inspired and mimetic designs in non‐viral gene delivery

“…[4][5][6] Thus, in recent years, researchers have aimed to develop virusmimicking non-viral carriers for enhancing transfection efficiency. [7][8][9][10] With inspiration from viral architectures and functions that respond to the microenvironment, various endogenous biological signals have been utilized as stimuli in the design of dynamic carriers. Pathological pH, redox potential, ROS, ATP and enzymes in the tumor site are all identified as special cues.…”