New co-delivery method for efficient siRNA and small molecule drug transport

Reposted from Discover BME (Institute of Biomedical Engineering).

Researchers at the University of Toronto have developed a method for co-delivering therapeutic RNA and potent drugs directly into cells, potentially leading to a more effective treatment of diseases in the future. This research, recently published in Advanced Materials, explores how ionizable drugs can be used to co-formulate small interfering RNA (siRNA) for more effective intracellular delivery.

siRNA is a powerful tool in medicine, capable of silencing specific genes responsible for disease. However, delivering these molecules into cells without degradation has been a significant challenge in drug delivery. Recent innovations in ionizable lipid design have improved siRNA delivery efficacy, but traditional nanoparticle formulations are limited in the amount of small molecule drugs they can load.

“We specifically targeted drug-resistant cells with the delivery of a relevant siRNA discovered by co-author and collaborator Dr. David Cescon at UHN/PMH. One of the biggest hurdles in siRNA therapy has been getting these molecules to where they need to go without losing their potency,” explained Professor Molly Shoichet, the study’s corresponding author. “Our approach using ionizable drugs as carriers marks a significant step forward in overcoming this barrier while also showing how drugs and RNA can be delivered together in the same nanoparticle formulation.”

When therapeutic formulations are absorbed by cells, small molecule drugs and siRNA are often trapped in small compartments called endosomes, preventing them from reaching their target destination and reducing their effectiveness.

The research team discovered that combining siRNA with ionizable drugs—compounds that change their charge based on pH levels—enhances the stability and delivery efficiency of siRNA inside cells, helping both the siRNA and drug escape the endosome and more effectively reach their destination. This novel method utilizes the protective properties of lipids to safeguard siRNA during its journey through the body and ensure the release of RNA and the drug together within the target cells.

“We found that our co-formulation method not only potently delivered siRNA to cells but also simultaneously delivered active ionizable drugs,” said Kai Slaughter, a PhD candidate in Dr. Shoichet’s lab and the lead author of the research. “This could be a game-changer for treating complex conditions where targeting multiple pathways is beneficial, such as cancer and viral infections.”