Current Aspects of siRNA Bioconjugate for In Vitro and In Vivo Delivery

Abstract

Studies on siRNA delivery have seen intense growth in the past decades since siRNA has emerged as a new class of gene therapeutics for the treatment of various diseases. siRNA bioconjugate, as one of the major delivery strategies, offers the potential to enhance and broaden pharmacological properties of siRNA, while minimizing the heterogeneity and stability-correlated toxicology. This review summarizes the recent developments of siRNA bioconjugate, including the conjugation with antibody, peptide, aptamer, small chemical, lipidoid, cell-penetrating peptide polymer, and nanoparticle. These siRNA bioconjugate, either administrated alone or formulated with other agents, could significantly improve pharmacokinetic behavior, enhance the biological half-life, and increase the targetability while maintaining sufficient gene silencing activity, with a concomitant improvement of the therapeutic outcomes and diminishment of adverse effects. This review emphasizes the delivery application of these siRNA bioconjugates, especially the conjugation strategy that control the integrity, stability and release of siRNA bioconjugates. The limitations conferred by these conjugation strategies have also been covered.

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

“…The exact mechanisms of how amphiphilic modification leads to subcellular organelle accumulation remain poorly established, but it is believed that the overall physicochemical properties and ligand–receptor interactions govern the intracellular sorting and trafficking pathways . For example, amphiphilic modification is an effective way for cytosolic targeting of small interfering RNAs (siRNA) . Lipophilic ligands modified siRNA associate with high density lipoproteins and cross the membrane directly into cytoplasm via non‐endocytotic pathway mediated by the scavenger receptor BI .…”

“…[82] For example, amphiphilic modification is an effective way for cytosolic targeting of small interfering RNAs (siRNA). [21,[84][85][86] Lipophilic ligands modified siRNA associate with high density lipoproteins and cross the membrane directly into cytoplasm via non-endocytotic pathway mediated by the scavenger receptor BI. [87] A wide range of lipophilic moieties including cholesterol, fatty acids, and steroids were used for siRNA conjugation and some of them have reached clinical stage.…”

Overcoming Barriers for siRNA Therapeutics: From Bench to Bedside

“…The siRNA is a negatively charged molecule, and it is almost impossible for siRNA to cross the biological membrane. The half-life of most naked or unmodified siRNA is between 5–10 min [ 46 ]. Table 2 illustrates the barriers faced by siRNA to reach its site of action.…”

“…Conjugation with polymer, especially PEG, is a common concept to increase the half-life of siRNA in blood and enhance the pharmacokinetic profiles [ 46 , 75 ]. A study demonstrated that conjugating siRNA with 20k PEG resulted in a slower rate of renal clearance (50% remained 1 h after injection) as compared to unmodified siRNA (<10% remained 15 min after injection) [ 76 ].…”

Alternative Anti-Infective Treatments to Traditional Antibiotherapy against Staphylococcal Veterinary Pathogens

“…However, the efficient delivery of siRNAs to their targeting cell is still one of the significant limitations of this strategy because siRNAs could be degraded by extracellular nucleases present in host tissues [ 94 , 95 ]. Therefore, new strategies have been developed to improve siRNAs’ delivery, including different conjugation methods with immunoproteins, peptide ligands, or aptamers [ 95 , 96 , 97 ]. Besides, siRNAs could also be encapsulated in gold or silver-based nanoparticles, liposomes, or cyclodextrin complexes that may protect their cargo against nuclease attacks [ 95 , 96 , 97 ].…”