Charge‐Conversion Strategies for Nucleic Acid Delivery

Nucleic acids are now considered as one of the most potent therapeutic modalities, as their roles go beyond storing genetic information and chemical energy or as signal transducer. Attenuation or expression of desired genes through nucleic acids have profound implications in gene therapy, gene editing and even in vaccine development for immunomodulation. Although nucleic acid therapeutics bring in overwhelming possibilities towards the development of molecular medicines, there are significant loopholes in designing and effective translation of these drugs into the clinic. One of the major pitfalls lies in the traditional design concepts for nucleic acid drug carriers, viz. cationic charge induced cytotoxicity in delivery pathway. Targeting this bottleneck, several pioneering research efforts have been devoted to design innovative carriers through 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 interesting approaches.