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

Oligonucleotide therapeutics are a new class of drugs that enable robust and sustained modulation of gene expression. However, achieving efficient delivery of small interfering RNAs (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 triple negative breast cancer mammary tumors. siRNAs were designed to selectively target insulin receptor substrate 2 (IRS2), a signaling adapter of insulin and insulin-like growth factor (IGF) 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.