Development Of A MiR122 Responsive DNA Nanodevice For Mitigating Drug-Induced Liver Injury

Drug-induced liver injury(DILI)is a common liver adverse reaction after the liver is exposed to excessive drugs,which can cause a large number of liver cell deaths and even liver failure.The hepatotoxicity of drugs is also one of the important indicators of new drug marketing.Many medicines can cause liver damage via variable mechanisms,and there are currently no specific diagnostic indicators and therapeutics for DILI.miR122 accounts for more than 50% of the miRNAs in the liver and is liver-specific.When DILI occurs,miR122 can be released into the circulation by damaged liver cells and can be detected earlier than the traditional liver biochemical index ALT/AST,which is a new DILI biomarker.Therefore,developing a drug specifically to treat DILI and promote liver regeneration is highly desirable.In this paper,we developed and characterized a miR122-responsive DNA nanodevice.The successful assembly of the DNA nanodevice and the responsiveness toward miR122 were first validated in vitro.Subsequently,we explored the MET receptor signaling activation in liver cells upon treatment with miR122-responsive DNA nanodevices.The results showed that the aptamer dimer formed after the response of DNA nanodevice could target the MET receptor and activate its signaling pathway in a time-dependent/concentration-dependent manner.Then,the effects of DNA nanodevice on the cellular behaviors after activation of relevant signaling pathways were studied.The results suggest that DNA nanodevice can effectively promote cell proliferation and migration.Furthermore,APAP-induced liver cells injury was constructed to evaluate the function of miR122-responsive DNA nanodevices.The data show that cell proliferation is significantly elevated to mitigate cell injury.Finally,the function of the DNA nanodevice was examined at the animal level by constructing the APAP-induced DILI mouse model.The robust increase of plasma miR122 in the DILI model was first verified,which indicates the model can be used to examine the functionality of miR122-responsiveness.The DNA nanodevice was injected into the tail vein and decreased circulating miR122 in plasma by binding with it.The difference in liver injury biomarkers,e.g.,ALT,liver tissue structure and immunostaining of ki67 that demonstrated the miR122-responsive DNA nanodevices could promote the regeneration of the injured liver.In summary,this thesis describes a miRNA-responsive DNA nanodevice,which expands a new therapeutic idea for liver recovery after DILI and miRNA-based disease treatment.