A Bottlebrush-like Polymer Makes It Possible for Oligonucleotides to Treat KRAS-mutant Lung Cancer

What is it about?

Developing small molecule inhibitors for oncogenic KRAS has been difficult, and gene regulation by oligonucleotides is seen as a possible alternative approach. However, the oligonucleotide drug modality faces significant challenges in potency and in the delivery to non-liver sites. Here, we describe a library of molecular brush-conjugated ASOs targeting wild-type KRAS mRNA. The architecture of the molecular brush suppresses nearly all side effects associated with DNA-protein interactions, and substantially enhances the potency and tumor uptake of the ASO. We compared our system with the state-of-the-art ASO using identical tumor models, where our constructs can reduce the dosage requirement by 40-fold to achieve a similar phenotypic response. We also demonstrate that these nanoconstructs are safe and well-tolerated in mice and are free of anti-carrier immunity.

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Photo by julien Tromeur on Unsplash

Photo by julien Tromeur on Unsplash

Why is it important?

The bottlebrush conjugates delivers the oligonucleotide to a variety of tissues/organs typically not accessible by this type of drug. With improved potency and reduced side effects, we envision that the conjugates can help expand the horizon of the oligonucleotide drug modality beyond the liver disease/rare genetic disease "comfort zone".