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Purdue researchers mimic virus strategy to delivering nucleic acid-based therapy to cancer cells

NEWS - Researchers from Purdue University in Indiana have developed a patent-pending platform technology that mimics the bilayer structure of viruses to target nucleic acid (NA)-based therapies to cancer cells. The researchers have delivered an NA-based therapy called LENN to bladder cancer cells.

Purdue researchers mimic virus strategy to delivering nucleic acid-based therapy to cancer cells

“LENN consists of two protective layers. The inner shell encloses the nucleic acid, the outer shell protects it from the immune system so it can circulate freely and reach the cancer cells. We are mimicking virus particles that have been doing this for millions of years,” said David Thompson.

The agile nanocarriers, which are flexible in targeting, payload size and disassembly kinetics, could provide an alternative route for nucleic acid delivery using vehicles that are bioproducible, biodegradable, biocompatible and can be tuned to different cells depending on specific tumor markers.

“Unfortunately, only 1% or less of the NA payload that enters the cell makes it to the cytosol where it is active. This new approach borrows from the principle of viruses. Our non-viral delivery system protects and efficiently releases the NA therapeutic within the cytoplasm of the target cell,” Thompson said.

Nucleic acid-based therapies are revolutionizing biomedical research through their ability to control cellular function at the genetic level. Thompson’s team has developed a therapy that consists of multiple constructs and is being explored to expand the human genome.

The interior of the LENN system is made of a complex of nucleic acids and cyclodextrins. The exterior is elastin, one of the most abundant proteins in the body. This design offers several advantages. Elastin is so abundant that antibodies don’t recognize it. The immune system won’t recognize it as a foreign nanoparticle.

“LENN delivers payloads as short as 19-nucleotide RNAs and large plasmids over 5,000 base pairs. The LENN system is engineered in a way that can be produced bioavailable. Cyclodextrins are from corn and elastin-like polypeptides are from bacterial fermentation. This is unlike most traditional pharmaceuticals that are derived from petroleum,” Thompson said.

Previous attempts at NA therapies have used lipid- or polymer-based carriers. Unfortunately, those approaches have very low efficacy, rapid immune clearance, and poor storage stability. Modified nucleic acids have shown some promise in experiments, but the safety of the approach has not been proven clinically.

The new paper joins four previously published papers based on Thompson’s research on the components of the LENN system. Bladder cancer is the first target of the LENN system. Thompson and his team are expanding efforts to other cancer types to explore the scope of the technology.

“We are learning to work with the material and optimize it. Bladder cancer therapy is a more localized therapeutic approach than subcutaneous or IV injection therapy. However, our plans include scaling up that difficulty to other cancer types,” Thompson said.

Original research

Aayush Aayush, Saloni Darji, Kiera M. Estes, Emily Yeh, David H. Thompson (2024). Development of an Elastin-like Polypeptide-Based Nucleic Acid Delivery System Targeted to EGFR+ Bladder Cancer Cells Using a Layer-by-Layer Approach. Biomacromolecules, DOI:10.1021/acs.biomac.4c00165

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