siRNA therapeutics: insights, challenges, remedies and future prospects

ABSTRACTIntroduction 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.KEYWORDS: Barriersclinical trialsgene silencingnanoparticlesRNA interferencesiRNA-regulatory approval AcknowledgementThe 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 interestThe 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 disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Abbreviations Terms=Full formALAS-1=Aminolevulinic acid synthase-1AuNPs=Gold nanoparticlesBBB=Blood-brain-barrierBp=Base pairCaP=Calcium phosphateCD=CyclodextrinsCNTs=Carbon nanotubesCQAs=Critical Quality AttributesDNA=Deoxyribonucleic acidDOPE=Dioleyl-sn-glycerol-3-phosphate ethanolamineDOTAP=1,2-dioleoyl-3-trimethylammonium-propaneDOTMA=1,2-di-O-octadecenyl-3-trimethylammonium-propaneDox=DoxorubicinDSPC=1,2-stearoyl-sn-glycero-3-phosphocholineEPR=Enhanced permeability and retentionHBV=Hepatitis B virusHER2=Human epidermal growth factor receptor 2kDa=Kilo DaltonsLbL=Layer by layermiRNA=Micro RNAMOF=Metal-organic frameworkMnis=Modified neuropathy impairment scoremRNA=Messenger RNAMSN=Mesoporous silica nanoparticlesncRNA=Non-coding RNANDs=NanodiamondsNPs=NanoparticlesNt=NucleotideOTC=Over the counterPAMAM=Poly (amidoamine)PBG=PorphobilinogenPEG=Polyethylene glycolPEI=PolyethyleneiminePH1=Primary hyperoxaluria type 1PK-PD=Pharmacokinetic-PharmacodynamicPLGA=Poly(dl-lactic-co-glycolic) acidPLL=Poly (L-lysine)PPI=Poly (propylene imine)pSi=Porous siliconPTGS=Post transcriptional gene silencingQDs=Quantum dotsRES=Reticuloendothelial systemRISC=RNA induced silencing complexRMM2=M2 subunit of ribonucleotide reductaseRNA=Ribonucleic acidRNAi=RNA interferencerRNA=Ribosomal RNAsiRNA=Small interfering RNASLNs=Solid lipid nanoparticlesSNALPs=Stable Nucleic Acid Lipid ParticlestFNAs=tetrahedral framework nucleic acidsTGS=Transcriptional gene silencingTNBC=Triple negative breast cancerTRBP=Tar RNA binding proteintRNA=Transfer RNAUS-FDA=The United States Food and Drug AdministrationVEGF=Vascular endothelium growth factorAdditional informationFundingThis paper was not funded.