Oligonucleotide drugs have been used widely as therapeutic agents for gene therapy,while their instability in biological media and inefficiency for intracellular delivery remain major hurdles for practical in vivo app...Oligonucleotide drugs have been used widely as therapeutic agents for gene therapy,while their instability in biological media and inefficiency for intracellular delivery remain major hurdles for practical in vivo applications.Herein,we report a circular Y-shaped aptamer–DNAzyme conjugate(cYAD)for highly efficient in vivo gene silencing via RNA cleavage,which can been employed in various disease treatments,including cancer,inflammation,as well as viral infections.Systematic studies revealed that cyclization of the DNA structure could improve the stability of oligonucleotide drugs in vivo.Besides,the bivalent aptamer motifs provided a specific and enhanced tumor cell targeting ability for accumulation and retention of the oligonucleotide drugs at the tumor site.As a proof of concept,a widely applicable Na+-dependent fluorescent sensor,NaA43 DNAzyme,was used to inhibit MET gene expression in mice tumor model tissues,which exhibited highly efficient gene silencing performance in vivo,which confirmed our findings with cYAD.This strategy provides a novel approach for the construction of oligonucleotide drugs for practical therapeutic applications.展开更多
基金supported by grants from the National Natural Science Foundation of China(nos.81601597,21904119,319009919,21621003,and U1704178)Innovation Talent Support Program of Henan Province(no.19HASTIT006)+2 种基金Key Scientific Research Projects(Education Department of Henan Province,nos.17A350003 and 20A350009)Key Scientific Research Projects(Science and Technology Department of Henan Province,no.192102310147)Postdoctoral Science Foundation of China(nos.2018T110745 and 2017M622380).
文摘Oligonucleotide drugs have been used widely as therapeutic agents for gene therapy,while their instability in biological media and inefficiency for intracellular delivery remain major hurdles for practical in vivo applications.Herein,we report a circular Y-shaped aptamer–DNAzyme conjugate(cYAD)for highly efficient in vivo gene silencing via RNA cleavage,which can been employed in various disease treatments,including cancer,inflammation,as well as viral infections.Systematic studies revealed that cyclization of the DNA structure could improve the stability of oligonucleotide drugs in vivo.Besides,the bivalent aptamer motifs provided a specific and enhanced tumor cell targeting ability for accumulation and retention of the oligonucleotide drugs at the tumor site.As a proof of concept,a widely applicable Na+-dependent fluorescent sensor,NaA43 DNAzyme,was used to inhibit MET gene expression in mice tumor model tissues,which exhibited highly efficient gene silencing performance in vivo,which confirmed our findings with cYAD.This strategy provides a novel approach for the construction of oligonucleotide drugs for practical therapeutic applications.
