Therapeutic delivery of albumin-binding siRNA targeting IRS2 to diverse cell types reduces mammary tumor growth

Tocheny, C. M.; Buchwald, J. E.; Dahlke, C. D.; Fakih, H. H.; Morgan, J. S.; Summers, A.; Wisniewski, C. A.; Jackson, S. O.; Lee, J.-S.; Card, M.-A.; Echeverria, D.; Peterson, C.; Mercurio, A. M.; Khvorova, A.; Shaw, L. M.

doi:10.1101/2025.07.29.667434

bioRxiv · 10.1101/2025.07.29.667434

Therapeutic delivery of albumin-binding siRNA targeting IRS2 to diverse cell types reduces mammary tumor growth

Tocheny, C. M.·Buchwald, J. E.·Dahlke, C. D.·Fakih, H. H.·Morgan, J. S.·Summers, A.·Wisniewski, C. A.·Jackson, S. O.·Lee, J.-S.·Card, M.-A.·Echeverria, D.·Peterson, C.·Mercurio, A. M.·Khvorova, A.·Shaw, L. M.

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Abstract

Oligonucleotide therapeutics are a new class of drugs that enable robust and sustained modulation of gene expression. However, achieving efficient delivery of siRNAs to tumors is a challenge for therapy. Here, we demonstrate that fully chemically modified siRNAs conjugated with an albumin-binding dendrimer are efficiently delivered to both neoplastic and stromal/immune cells within primary TNBC mammary tumors. siRNAs were designed to selectively target IRS2, a signaling adaptor of insulin and insulin-like growth factor signaling that has been implicated in aggressive breast cancers. These siRNAs reduced Irs2 expression in tumor and stromal cells without causing hyperglycemia, resulting in reduced tumor growth that was associated with decreased vascularization and alterations in macrophage polarization and the expression of EMT proteins. This work demonstrates that siRNAs can be delivered to neoplastic and specific stromal populations in mammary tumors and that they can effectively and specifically silence a driver of aggressive breast cancer.

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Tocheny, C. M., Buchwald, J. E., Dahlke, C. D., Fakih, H. H., Morgan, J. S., Summers, A., Wisniewski, C. A., Jackson, S. O., Lee, J.-S., Card, M.-A., Echeverria, D., Peterson, C., Mercurio, A. M., Khvorova, A., Shaw, L. M.. 2025-08-01. Therapeutic delivery of albumin-binding siRNA targeting IRS2 to diverse cell types reduces mammary tumor growth. https://doi.org/10.1101/2025.07.29.667434

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