title: In situ amplification of intracellular microRNA with MNAzyme nanodevices for multiplexed imaging, logic operation, and controlled drug release.
abstract: MicroRNAs (miRNAs), as key regulators in gene expression networks, have participated in many biological processes, including cancer initiation, progression, and metastasis, indicative of potential diagnostic biomarkers and therapeutic targets. To tackle the low abundance of miRNAs in a single cell, we have developed programmable nanodevices with MNAzymes to realize stringent recognition and in situ amplification of intracellular miRNAs for multiplexed detection and controlled drug release. As a proof of concept, miR-21 and miR-145, respectively up- and down-expressed in most tumor tissues, were selected as endogenous cancer indicators and therapy triggers to test the efficacy of the photothermal nanodevices. The sequence programmability and specificity of MNAzyme motifs enabled the fluorescent turn-on probes not only to sensitively profile the distributions of miR-21/miR-145 in cell lysates of HeLa, HL-60, and NIH 3T3 (9632/0, 14147/0, 2047/421 copies per cell, respectively) but also to visualize trace amounts of miRNAs in a single cell, allowing logic operation for graded cancer risk assessment and dynamic monitoring of therapy response by confocal microscopy and flow cytometry. Furthermore, through general molecular design, the MNAzyme motifs could serve as three-dimensional gatekeepers to lock the doxorubicin inside the nanocarriers. The drug nanocarriers were exclusively internalized into the target tumor cells via aptamer-guided recognition and reopened by the endogenous miRNAs, where the drug release rates could be spatial-temporally controlled by the modulation of miRNA expression. Integrated with miRNA profiling techniques, the designed nanodevices can provide general strategy for disease diagnosis, prognosis, and combination treatment with chemotherapy and gene therapy.
authors.affiliation: State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University , Nanjing 210093, People's Republic of China.
authors.forename: Penghui
authors.initials: P
authors.lastname: Zhang
authors.forename: Zhimei
authors.initials: Z
authors.lastname: He
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Jiangning
authors.initials: J
authors.lastname: Chen
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.forename: Xuena
authors.initials: X
authors.lastname: Zhu
authors.forename: Chen-Zhong
authors.initials: CZ
authors.lastname: Li
authors.forename: Qianhao
authors.initials: Q
authors.lastname: Min
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002460:Cell Line; D021881:DNA, Catalytic / Q000737:chemistry / Q000378:metabolism*; D003692:Delayed-Action Preparations; D004317:Doxorubicin / Q000737:chemistry; D006046:Gold / Q000737:chemistry; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008128:Logic; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D057054:Molecular Imaging / Q000379:methods*; D015335:Molecular Probes / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods*; D043942:Nanotubes / Q000737:chemistry; D009690:Nucleic Acid Conformation; D016062:Porosity; D018570:Risk Assessment; D012822:Silicon Dioxide / Q000737:chemistry; D013499:Surface Properties
chemical_list: D021881:DNA, Catalytic; D003692:Delayed-Action Preparations; D035683:MicroRNAs; D015335:Molecular Probes; D006046:Gold; D012822:Silicon Dioxide; D004317:Doxorubicin
keywords: DNAzyme; drug delivery; intracellular imaging; logic operation; microRNAs