(PhotoRNADelivery) Functionalization of microRNAs using photoresponsive nanopores as a new therapeutic strategy for fatty liver

What is PhotoRNADelivery about?

Liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD), are growing at an alarming rate in Western countries. Characterized by dysregulation of metabolic networks within the liver, disease progression is common and often leads to cancer of the liver, including hepatocellular carcinoma.

MASLD affects an array of cellular pathways and, as such, has been largely refractory to pharmacological treatments. New treatment options are vital for reversing this concerning medical pandemic. In this proposal, the Belardi Lab and the Castro Lab will collaborate to deliver anti-miRNA therapies to the cytoplasm of liver cells.

Here, the teams will rely on recent nanotechnology developed by the Belardi Lab, namely light-dependent nanopore delivery of molecular cargo. In this delivery method, synthetic cells are fabricated with light sensitive- nanopores that can pair with channels on liver cells, offering the possibility of direct cytoplasmic transfer.

In this project, researchers will develop new methodology that enables NIR light-dependent delivery for the treatment of MASLD. Overall, light-dependent nanopore assembly is a highly promising therapeutic approach for treating and/or halting MASLD progression and will pave the way for similar nanotechnology therapeutic strategies for many other diseases.

What critical challenges is PhotoRNADelivery addressing?

Currently, there are few pharmacological treatments available for MASLD. As such, disease often progresses to cirrhosis and hepatocellular carcinoma (HCC). HCC, the most common primary liver cancer, is considered the third leading cause of cancer-related deaths worldwide. New therapeutic approaches are urgently needed to treat MASLD and avoid disease progression.

Recently, Castro’s lab and others have reported that RNA-based therapies, for example miRNA, can be used to treat animal models of MASLD. However, delivery of miRNA to liver cytoplasm, the site of action, stands as a pressing and unsolved technical problem to-date.

How will PhotoRNADelivery transfer miRNA therapy to disease liver cells?

At the end of the project period, we expect to have developed a new nanotechnology platform that relies on near-IR light to activate transfer of miRNA therapy to disease liver cells. This will necessarily involve new chemistries that allow for near-IR light activation of engineered nanopores. Also, the final synthetic cell product will be a new nanotechnology platform that can be applied to other miRNAs and other cell types more broadly. We expect multiple peer-reviewed manuscripts, conference presentations, and training experiences to result from this project.

How is PhotoRNADelivery expected to impact its research area?

By combining expertise in nanotechnology and liver disease biology, a new method of specific, localized treatment for liver disease will be realized. This will have significant impact on patients suffering from MASLD. Further, the nanotechnology platform
will be designed such that the synthetic cells will offer a general method for delivering miRNA therapies to other diseases in humans, where direct cytoplasmic transfer is advantageous. RNA-based treatments represent the new frontier in therapy, particularly after the success of the COVID RNA vaccines, and this nanotechnology will be a critical force behind their translation to the clinic.