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ABSTRACT
Introduction
Among conventional and novel therapeutic approaches, the siRNA strategy stands out for treating disease by silencing the gene responsible for the corresponding disorder. Gene silencing is supposedly intended to target any disease-causing gene, and therefore, several attempts and investments were made to exploit siRNA gene therapy and advance it into clinical settings. Despite the remarkable beneficial prospects, the applicability of siRNA therapeutics is very challenging due to various pathophysiological barriers that hamper its target reach, which is the cytosol, and execution of gene silencing action.
Areas covered
The present review provides insights into the field of siRNA therapeutics, significant in vivo hurdles that mitigate the target accessibility of siRNA, and remedies to overcome these siRNA delivery challenges. Nonetheless, the current review also highlights the on-going clinical trials and the regulatory aspects of siRNA modalities.
Expert opinion
The siRNAs have the potential to reach previously untreated target sites and silence the concerned gene owing to their modification as polymeric or lipidic nanoparticles, conjugates, and the application of advanced drug delivery strategies. With such mounting research attempts to improve the delivery of siRNA to target tissue, we might shortly witness revolutionary therapeutic outcomes, new approvals, and clinical implications.
GRAPHICAL ABSTRACT
Acknowledgement
The authors are thankful to DST-FIST for their departmental support.
Article highlights
The siRNA strategy possesses unique attributes for treating disease by silencing the gene responsible for the corresponding disorder.
The systemically administered siRNA fails to reach the target site (the cytosol) owing to substantial pathophysiological barriers.
The major extracellular barriers that prevent siRNA from reaching the target site include enzymatic degradation, rapid renal clearance, the inability to cross biological membranes, instigation of the immunogenic cascade, and sequestration by plasma proteins.
The chief intracellular obstacles to siRNA gene silencing action once it reaches the target tissue include endosome entrapment, accessibility of the exact intracellular site of action (the cytosol), and off-target effects.
Chemical modification by conjugation, encapsulation into nanocarriers, and advanced approaches such as tFNAs and LbL nanoparticle assembly have the potential to significantly improve siRNA bioavailability and therapeutic efficacy.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Abbreviations
| Terms | = | Full form |
| ALAS-1 | = | Aminolevulinic acid synthase-1 |
| AuNPs | = | Gold nanoparticles |
| BBB | = | Blood-brain-barrier |
| Bp | = | Base pair |
| CaP | = | Calcium phosphate |
| CD | = | Cyclodextrins |
| CNTs | = | Carbon nanotubes |
| CQAs | = | Critical Quality Attributes |
| DNA | = | Deoxyribonucleic acid |
| DOPE | = | Dioleyl-sn-glycerol-3-phosphate ethanolamine |
| DOTAP | = | 1,2-dioleoyl-3-trimethylammonium-propane |
| DOTMA | = | 1,2-di-O-octadecenyl-3-trimethylammonium-propane |
| Dox | = | Doxorubicin |
| DSPC | = | 1,2-stearoyl-sn-glycero-3-phosphocholine |
| EPR | = | Enhanced permeability and retention |
| HBV | = | Hepatitis B virus |
| HER2 | = | Human epidermal growth factor receptor 2 |
| kDa | = | Kilo Daltons |
| LbL | = | Layer by layer |
| miRNA | = | Micro RNA |
| MOF | = | Metal-organic framework |
| Mnis | = | Modified neuropathy impairment score |
| mRNA | = | Messenger RNA |
| MSN | = | Mesoporous silica nanoparticles |
| ncRNA | = | Non-coding RNA |
| NDs | = | Nanodiamonds |
| NPs | = | Nanoparticles |
| Nt | = | Nucleotide |
| OTC | = | Over the counter |
| PAMAM | = | Poly (amidoamine) |
| PBG | = | Porphobilinogen |
| PEG | = | Polyethylene glycol |
| PEI | = | Polyethyleneimine |
| PH1 | = | Primary hyperoxaluria type 1 |
| PK-PD | = | Pharmacokinetic-Pharmacodynamic |
| PLGA | = | Poly(dl-lactic-co-glycolic) acid |
| PLL | = | Poly (L-lysine) |
| PPI | = | Poly (propylene imine) |
| pSi | = | Porous silicon |
| PTGS | = | Post transcriptional gene silencing |
| QDs | = | Quantum dots |
| RES | = | Reticuloendothelial system |
| RISC | = | RNA induced silencing complex |
| RMM2 | = | M2 subunit of ribonucleotide reductase |
| RNA | = | Ribonucleic acid |
| RNAi | = | RNA interference |
| rRNA | = | Ribosomal RNA |
| siRNA | = | Small interfering RNA |
| SLNs | = | Solid lipid nanoparticles |
| SNALPs | = | Stable Nucleic Acid Lipid Particles |
| tFNAs | = | tetrahedral framework nucleic acids |
| TGS | = | Transcriptional gene silencing |
| TNBC | = | Triple negative breast cancer |
| TRBP | = | Tar RNA binding protein |
| tRNA | = | Transfer RNA |
| US-FDA | = | The United States Food and Drug Administration |
| VEGF | = | Vascular endothelium growth factor |