Charge‐Conversion Strategies for Nucleic Acid Delivery

Abstract

Nucleic acids are considered as one of the most potent therapeutic modalities, as their roles go beyond storing genetic information and chemical energy or as signal transducers. Attenuation or expression of desired genes through nucleic acids have profound implications in gene therapy, gene editing, and even in vaccine development. Although nucleic acid therapeutics bring in overwhelming possibilities toward the development of molecular medicines, there are significant loopholes in their effective clinical translation. One of the major pitfalls lies in the traditional design concepts of nucleic acid drug carriers, namely, cationic charge induced cytotoxicity. Targeting this bottleneck, several innovative carrier designs have been proposed accommodating charge‐conversion approaches, whereby built‐in functionalities convert from cationic to neutral or anionic, or even from anionic to cationic enabling the carrier to overcome several critical barriers for therapeutics delivery, such as serum deactivation, instability in circulation, low transfection, and poor endosomal escape. This review will critically analyze various molecular designs of charge‐converting nanocarriers in a classified approach for the successful delivery of nucleic acids. Accompanied by the narrative on recent clinical nucleic acid candidates, the review concludes with a discussion on the pitfalls and scope of these emerging approaches.

Designing Synthetic Polymers for Nucleic Acid Complexation and Delivery: From Polyplexes to Micelleplexes to Triggered Degradation

“…Designing polymeric delivery systems with charge-conversion properties via macromolecular design and degradable subunits is thus promising for addressing the dilemma between safety and efficacy. 67 In addition, reconfiguring conventional linear polymers to complex architectures, such as comb-like, bottlebrush, and multiblock structures, successfully modulates polyplex properties and intracellular activities and collectively points to advantages of merging chemical functionalization with architecture designs. 23,28,35 Although the library of polymeric vectors has rapidly expanded and resulted in considerable improvement in transfection performance, there remains substantial space for improvement, especially with respect to increasing the…”

“…However, the long-term potential toxicity of the degraded products requires careful examination: polymer degradation and the associated polyplex properties should be studied under biologically relevant conditions. Designing polymeric delivery systems with charge-conversion properties via macromolecular design and degradable subunits is thus promising for addressing the dilemma between safety and efficacy . In addition, reconfiguring conventional linear polymers to complex architectures, such as comb-like, bottlebrush, and multiblock structures, successfully modulates polyplex properties and intracellular activities and collectively points to advantages of merging chemical functionalization with architecture designs. ,, …”

What’s Next after Lipid Nanoparticles? A Perspective on Enablers of Nucleic Acid Therapeutics

“…These ionizable liposomes are anionic or neutral that become slightly cationic in the tumor environment to enhance cellular internalizations . This charge-conversion strategy presents a new direction in designing delivery vectors for targeted therapeutics …”

“…GFP siRNA was encapsulated in a cationic lipid inner core surrounded by a hydrophobic poly­(lactic- co -glycolic acid) (PLGA) shell and a neutral lipid encasing to form a stealth surface layer (Figure A). , Following the success of the initial concept, an improved version of the lipid–polymer hybrid using lipidoid G0-C14 in the nanoparticle core showed a significant increase in stability with a release half-life of ∼9 days, compared to ∼8 h for lipofectamine 2000 . , In vivo validation of the hybrid formulations in delivering PHB1 siRNA established the potential of the nanodelivery platform with an ∼76% decrease in PHB1 expression in the treated group . Inspired by such promise, scientists have explored several structural variations in polymer–lipid combinations. , Among them, charge-reversing polymers appeared to be particularly interesting because of their ability to switch the surface charge from cationic to anionic or vice versa, on demand, which mitigates the cation-mediated toxicity observed with traditional polymeric transfection agents. , To this end, our group envisaged a polymer system that uses a “bait-and-switch” strategy to incarcerate siRNA in a tightly packed polymeric core using a novel ad hoc electrostatic encapsulation process that eliminates cationic charges. , To further improve the system by harnessing the advantages of a lipid coating, the formulation was completed by encasing a zwitterionic lipid shell using hydrophobic alkyl chains on the polymer as handles to obtain “virus-inspired” symbiotic self-assemblies (Figure C) . These nanoparticles show efficient silencing of three different genes GFP , PLK1 , and MDR1 with negligible cytotoxicity compared to commercial transfection agents (Figure D,E).…”

Sedimentation of Fine Arsenopyrite with PEI and the Flotation Significance

“…The optimal value of PEI-3 was 90%, while the sedimentation yield without flocculant was only 12.6%. When pH exceeded 7.5, the decrease in sedimentation efficiency may have been caused by the decationization of the PEIs under alkaline conditions [15,16]. Therefore, the pH of 7.5 was determined as the optimum condition for the sedimentation tests.…”