Current status and trends in small nucleic acid drug development:Leading the future

Small nucleic acid drugs,composed of nucleotides,represent a novel class of pharmaceuticals that differ significantly from conventional small molecule and antibody-based therapeutics.These agents function by selectively targeting specific genes or their corresponding messenger RNAs(mRNAs),further modulating gene expression and regulating translation-related processes.Prominent examples within this category include antisense oligonucleotides(ASO),small interfering RNAs(siRNAs),micro-RNAs(miRNAs),and aptamers.The emergence of small nucleic acid drugs as a focal point in contemporary biopharmaceutical research is attributed to their remarkable specificity,facile design,abbreviated development cycles,expansive target spectrum,and prolonged activity.Overcoming challenges such as poor stability,immunogenicity,and permeability issues have been addressed through the integration of chemical modifications and the development of drug delivery systems.This review provides an overview of the current status and prospective trends in small nucleic acid drug development.Commencing with a historical context,we introduce the primary classifications and mechanisms of small nucleic acid drugs.Subsequently,we delve into the advantages of the U.S.Food and Drug Administration(FDA)approved drugs and mainly discuss the challenges encountered during their development.Apart from researching chemical modification and delivery system that efficiently deliver and enrich small nucleic acid drugs to target tissues,promoting endosomal escape is a critical scientific question and important research direction in siRNA drug development.Future directions in this field will prioritize addressing these challenges to facilitate the clinical transformation of small nucleic acid drugs.

A comprehensive analysis of the Bencao(herbal)small RNA Atlas reveals novel RNA therapeutics for treating human diseases

Cross-kingdom herbal mi RNA was first reported in 2012.Using a modified herbal extraction protocol,we obtained 73,677,287sequences by RNA-seq from 245 traditional Chinese Medicine(TCM),of which 20,758,257 were unique sequences.We constructed a Bencao(herbal)small RNA(s RNA)Atlas(http://bencao.bmicc.cn),annotated the sequences by sequence-based clustering,and created a nomenclature system for Bencao s RNAs.The profiles of 21,757 mi RNAs in the Atlas were highly consistent with those of plant mi RNAs in mi RBase.Using software tools,our results demonstrated that all human genes might be regulated by s RNAs from the Bencao s RNA Atlas,part of the predicted human target genes were experimentally validated,suggesting that Bencao s RNAs might be one of the main bioactive components of herbal medicines.We established roadmaps for oligonucleotide drugs development and optimization of TCM prescriptions.Moreover,the decoctosome,a lipo-nano particle consisting of 0.5%–2.5%of the decoction,demonstrated potent medical effects.We propose a Bencao(herbal)Index,including small-molecule compounds(SM),protein peptides(P),nucleic acid(N),non-nucleic and non-proteinogenic large-molecule compounds(LM)and elements from Mendeleev's periodic table(E),to quantitatively measure the medical effects of botanic medicine.The Bencao s RNA Atlas is a resource for developing gene-targeting oligonucleotide drugs and optimizing botanical medicine,and may provide potential remedies for the theory and practice of one medicine.

Orally administered BZL-s RNA-20 oligonucleotide targeting TLR4 effectively ameliorates acute lung injury in mice

The global COVID-19 pandemic emerged at the end of December 2019.Acute respiratory distress syndrome(ARDS)and acute lung injury(ALI)are common lethal outcomes of bacterial lipopolysaccharide(LPS),avian influenza virus,and SARS-Co V-2.Toll-like receptor 4(TLR4)is a key target in the pathological pathway of ARDS and ALI.Previous studies have reported that herbal small RNAs(s RNAs)are a functional medical component.BZL-s RNA-20(Accession number:B59471456;Family ID:F2201.Q001979.B11)is a potent inhibitor of Toll-like receptor 4(TLR4)and pro-inflammatory cytokines.Furthermore,BZLs RNA-20 reduces intracellular levels of cytokines induced by lipoteichoic acid(LTA)and polyinosinic-polycytidylic acid(poly(I:C)).We found that BZL-s RNA-20 rescued the viability of cells infected with avian influenza H5N1,SARS-Co V-2,and several of its variants of concern(VOCs).Acute lung injury induced by LPS and SARS-Co V-2 in mice was significantly ameliorated by the oral medical decoctosome mimic(bencaosome;sphinganine(d22:0)+BZL-s RNA-20).Our findings suggest that BZLs RNA-20 could be a pan-anti-ARDS/ALI drug.

Oral administration of the herbal oligonucleotide XKC-sRNA-h3 prevents angiotensinⅡ-induced hypertension in mice

Hypertension has become a growing public health concern worldwide.In fact,hypertension is commonly associated with increased morbidity and mortality.Currently,oligonucleotide drugs have proven to be promising therapeutic agents for various diseases.In the present study,we aimed to demonstrate that a herbal small RNA(s RNA),XKC-sRNA-h3(B55710460,F221.I000082.B11),exhibits potent antihypertensive effects by targeting angiotensin-converting enzyme(ACE)in mice.When compared with captopril,oral administration of the sphingosine(d18:1)-XKC-s RNA-h3 bencaosome more effectively prevented angiotensin II-induced hypertensive cardiac damage and alleviated kidney injury in mice.Such findings indicated that XKC-sRNA-h3 may be a novel orally available ACE inhibitor type oligonucleotide drug for hypertension.