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Multifunctional miRNA-targeting nanodevices for pluripotent cancer theranostics

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An intelligent DNA therapy against cancer

Chemotherapy remains the only treatment option for many types of cancer, but its non-specific nature leads to adverse, highly unpleasant side-effects. A European study has developed an intelligent therapeutic platform against cancer that combines DNA drugs with the precision of nanoparticle-based delivery.

Health

miRNAs are short non-coding RNAs that regulate gene expression at the post-transcriptional level. There is established evidence that abnormal expression of certain miRNAs is associated with cancer. This renders them as promising anti-cancer targets and as biomarkers for prompt diagnosis.

Nanoparticle-mediated delivery of miRNAs

The MIRNANO project was undertaken with the support of the Marie Skłodowska-Curie programme to develop nanoparticles as vehicles for delivering these anti-miRNA nucleic acids. The latter will ensure knockdown of target miRNAs, inducing downstream suppression of tumour growth. “We have developed two types of miRNA-targeting nanoparticles that could be employed as therapeutic agents in precision medicine or as molecular diagnostics tools,” explains the research fellow Alessandro Bertucci. To do so, project researchers have employed biocompatible and biodegradable porous silicon nanoparticles capable of accommodating various payloads including synthetic nucleic acids. Tuning the molecular identity of the nucleic acid cargo determines nanoparticle application. MIRNANO focused on ovarian cancer, one of the leading causes of cancer-related mortality among women. The research team targeted miR-21, associated with cell proliferation, multidrug resistance, and tumour invasion. The engineered nanoparticles carried an artificial oligonucleotide complementary to miR-21 and were functionalised with a tumour-homing peptide on their surface which improved their accumulation in the tumour microenvironment. When tested in vivo in a xenograft mouse model of ovarian cancer, the engineered nanoparticles efficiently blocked miR-21 and completely inhibited tumour growth with no side effects. Researchers also exploited miR-21 as a cancer diagnostic/prognostic marker, engineering a synthetic DNA-based sensor that provides a fluorescence signal when binding to the target microRNA. Nanoparticle design optimisation facilitated tuneable release of the sensor and efficient detection of miR-21 in situ and in real time for over 20 days.

A tuneable therapeutic strategy

To successfully deliver the precision healthcare of the future, different scientific domains must come together. Nucleic acid engineering can improve in vivo stability of molecular drugs by using new classes of nucleic acid structures or artificial oligonucleotide mimics. Combining this intelligent system with nanotechnology allows the specific delivery of the DNA drugs or imaging compounds at the site of interest. The MIRNANO nanoparticle platform offers extensive versatility as it can target different miRNAs and tissues. The battery of chemical and biological methodologies developed during the project enable tailoring of these nanoparticle-based miRNA-targeting therapeutics to different needs. According to Bertucci, “by simply changing the sequence and the function of the synthetic nucleic acid payload, it is possible to obtain an incredibly vast repertoire of nanoparticles for a precise biomedical task.” This means that potential applications extend beyond cancer to tissue engineering and regenerative medicine, as well as other diseases with an aberrant miRNA expression pattern. With a view to the future, the research team plans to advance the MIRNANO DNA technologies and integrate different types of hardware, including electrochemical platforms, nanostructured materials and microfluidics devices. Long-term this will expand the range of molecular strategies that could make an impact on healthcare provision.

Keywords

MIRNANO, miRNA, nanoparticles, ovarian cancer, miR-21

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