Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs

Abstract

Nucleic acid and genetic medicines are increasingly being developed, owing to their potential to treat a variety of intractable diseases. A comprehensive understanding of the in vivo fate of these agents is vital for the rational design, discovery, and fast and straightforward development of the drugs. In case of intravascular administration of nucleic acids and genetic medicines, interaction with blood components, especially plasma proteins, is unavoidable. However, on the flip side, such interaction can be utilized wisely to manipulate the pharmacokinetics of the agents. In other words, plasma protein binding can help in suppressing the elimination of nucleic acids from the blood stream and deliver naked oligonucleotides and gene carriers into target cells. To control the distribution of these agents in the body, the ligand conjugation method is widely applied. It is also important to understand intracellular localization. In this context, endocytosis pathway, endosomal escape, and nuclear transport should be considered and discussed. Encapsulated nucleic acids and genes must be dissociated from the carriers to exert their activity. In this review, we summarize the in vivo fate of nucleic acid and gene medicines and provide guidelines for the rational design of drugs.

Interaction of γ-Polyglutamic Acid/Polyethyleneimine/Plasmid DNA Ternary Complexes with Serum Components Plays a Crucial Role in Transfection in Mice

“…Tremendous efforts have been made to understand the mechanisms underlying gene transfer. These mechanisms include interactions with blood components, cellular association and uptake, endocytic routes, endosomal escape, cytosolic and nuclear transport, and dissociation of cargo from carriers [ 41 ]. In this study, we focused on the interaction of complexes with blood components as the first step in in vivo gene transfer.…”

Physical and mechanical cues affecting biomaterial-mediated plasmid DNA delivery: insights into non-viral delivery systems

“…Similarly, compared to PLL, PEI polyplexes showed a lower cytoplasmic uptake, but a higher percentage of nuclear uptake [76]. Although this was beyond the scope of this review, it is noteworthy to mention that the in vivo fate of biomaterial-mediated gene delivery systems is also influenced by many other parameters, including eventual interaction with plasma proteins [235], or potential triggering of an innate immune response [236]. Only a better understanding of these processes may allow to the creation of novel robust engineered systems, potentially opening up a whole new area of biomaterial-guided gene delivery for non-viral systems.…”

The therapeutic prospects of N-acetylgalactosamine-siRNA conjugates

“…Subsequently, the synthesized three-antenna GalNAc can combine with the 3′ end of the antisense chain of siRNA to form a GalNAc-siRNA conjugate (Shchegravina et al, 2021). siRNA can be synthesized directly by a chemical approach or by breaking long double-stranded RNA obtained by enzyme transcription into 21-23 nt siRNA under the action of the GalNAc-siRNA LNPs loaded siRNA (Aldosari et al, 2021;Zhang et al, 2021a;Lokugamage et al, 2021) Benefits & Challenges -can be injected subcutaneously, with only small chances of plasma siRNA degradation, rapid absorption, high uptake, and long half-life, (Springer and Dowdy, 2018)-endosomal escape, hepatotoxicity from off-target effects, acidic subcellular compartments, and extensive clearance, affect GalNAc efficiency and sequence barriers (Ayyar et al, 2021;Fairman et al, 2021;Fattal and Fay, 2021;Fumoto et al, 2021;Liu et al, 2021;Nanavati et al, 2021;Schlich et al, 2021) -avoid siRNA degradation of and the stimulation of the immune system by siRNA-lack efficient nuclear penetration and sustainable transgene expression (limitations such as poor biodistribution and possible toxic discharge), immunogenic and pose safety concerns of liposome molecules and limited efficacy and biosafety since unconjugated liposomes cannot achieve targeted delivery (Ickenstein and Garidel, 2019;Hu et al, 2020;Blakney et al, 2021;Hassett et al, 2021;Maestro et al, 2021) Composition Specific arrangement of nucleoside, pO/PS linkage and monovalent GalNAc (Matsuda et al, 2015) polyethylene glycol-lipid conjugates (PEG-DMG), ionizable amino lipids (DLin-MC3-DMA), distearyl phosphatidylcholine (DSPC) and cholesterol…”

“…Although GalNAc conjugates possess better stability, other crucial factors, such as endosomal escape, hepatotoxicity from off-target effects, acidic subcellular compartments, and extensive clearance, affect GalNAc efficiency and sequence barriers ( Ayyar et al, 2021 ; Fairman et al, 2021 ; Fattal and Fay, 2021 ; Fumoto et al, 2021 ; Liu et al, 2021 ; Nanavati et al, 2021 ; Schlich et al, 2021 ).…”