The Multifaceted Histidine-Based Carriers for Nucleic Acid Delivery: Advances and Challenges

Abstract

Histidines incorporated into carriers of nucleic acids may enhance the extracellular stability of the nanoparticle, yet aid in the intracellular disruption of the nanoparticle, enabling the release of the nucleic acid. Moreover, protonation of histidines in the endosomes may result in endosomal swelling with subsequent lysis. These properties of histidine are based on its five-member imidazole ring in which the two nitrogen atoms may form hydrogen bonds or act as a base in acidic environments. A wide variety of carriers have integrated histidines or histidine-rich domains, which include peptides, polyethylenimine, polysaccharides, platform delivery systems, viral phages, mesoporous silica particles, and liposomes. Histidine-rich carriers have played key roles in our understanding of the stability of nanocarriers and the escape of the nucleic acids from endosomes. These carriers show great promise and offer marked potential in delivering plasmids, siRNA, and mRNA to their intracellular targets.

Nanoscale delivery platforms for RNA therapeutics: Challenges and the current state of the art

“…First, the buffering capacity of a polymer at acidic pH has been found to be a significant factor in its efficacy as a delivery vehicle. 88,90 Certain moieties, such as imidazole 91,92 and guanidine 93,94 groups, have been found to be particularly effective at facilitating complexation and endosomal escape. Bisphenol-A (BPA)-containing groups have also been found to be effective when incorporated into PBAEs; 86,95 interestingly, BPA-derived compounds may also improve efficacy when added as excipients to other NPs.…”

Charge Conversion Polymer–Liposome Complexes to Overcome the Limitations of Cationic Liposomes in Mitochondrial-Targeting Drug Delivery

“…The mPEG-b-P(MAAc-g-His)-NH 2 copolymers can be absorbed on and shield the positive charges of cationic liposomes through electrostatic interactions for fabricating pH-sensitive charge-conversion polymer–liposome complexes at neutral pH and to desorb from cationic liposomes via charged neutralization at low pH ( Figure 1 ). In addition, because histidine molecules caused the proton sponge effect at low pH [ 24 ], copolymers could induce CTPP-containing cationic liposomes escaping out of the endosomes to target and deliver the payload to mitochondria.…”

Imidazole-Based pH-Sensitive Convertible Liposomes for Anticancer Drug Delivery

“…Imidazoles carry pKa values around 5.0–6.5 and thus can protonate to assume a positive charge in response to weakly acidic pH in pathophysiological settings [ 21 ]. The incorporation of imidazole-based lipids into nano-formulations has enhanced their intracellular delivery of proteins and nucleic acids [ 22 , 23 ]. However, very few studies [ 24 ] have been reported on imidazole-based nano-formulations for anticancer drug delivery.…”