Small interfering RNAs (siRNAs) hold considerable therapeutic potential to selectively silence previously "undruggable" disease-associated targets, offering new opportunities to fight human diseases. This therapeutic strategy, however, is limited by the inability of naked siRNAs to passively diffuse across cellular membranes due to their large molecular size and negative charge. Delivery of siRNAs to liver through conjugation of siRNA to N-acetylgalactosamine (GalNAc) has been a success, providing robust and durable gene knockdown, specifically in hepatocytes. However, the poor delivery and silencing efficacy of siRNAs in other cell types has hindered their applications outside the liver. We previously reported that a genome-wide pooled knockout screen identified

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J. Lu, J. Lee, E.Y., D.L.W., M.K., D.P., J.B., I.C.R., J.X., J.F., J. Long, B.M., O.H., W.G., T.G., H.Z., B.W., J.C., and S.W. are employees at Amgen Inc. All authors owned Amgen shares when the study was conducted. However, these do not alter the authors’ adherence to all journal policies on sharing data and materials. None of the authors serve as a current editorial team member for this journal. A patent application entitled “compositions and methods for enhancing gene silencing activity of oligonucleotide compounds” has been filed (WO2023059629A1 WIPO (PCT)).