Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy

• Published in: Nature communications Vol. 15; no. 1; p. 1581
• Main Authors: Hoogenboezem, Ella N, Patel, Shrusti S, Lo, Justin H, Cavnar, Ashley B, Babb, Lauren M, Francini, Nora, Gbur, Eva F, Patil, Prarthana, Colazo, Juan M, Michell, Danielle L, Sanchez, Violeta M, McCune, Joshua T, Ma, Jinqi, DeJulius, Carlisle R, Lee, Linus H, Rosch, Jonah C, Allen, Ryan M, Stokes, Larry D, Hill, Jordan L, Vickers, Kasey C, Cook, Rebecca S, Duvall, Craig L
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 21.02.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Albumin; Albumins - genetics; Antineoplastic Agents; Apoptosis; Binding; Breast cancer; Cancer therapies; Cell Line, Tumor; Conjugates; Gene Silencing; Humans; Hydrophobicity; Lipids; Lipids - chemistry; Mcl-1 protein; Molecular structure; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Oncogenes; Pharmacokinetics; RNA, Small Interfering; Self-assembly; Serum albumin; Silence; siRNA; Structure-function relationships; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45609-0

The high potential of siRNAs to silence oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, divalent lipid-conjugated siRNAs are optimized for in situ binding to albumin to improve pharmacokinetics and tumor delivery. Systematic variation of the siRNA conjugate structure reveals that the location of the linker branching site dictates tendency toward albumin association versus self-assembly, while the lipid hydrophobicity and reversibility of albumin binding also contribute to siRNA intracellular delivery. The lead structure increases tumor siRNA accumulation 12-fold in orthotopic triple negative breast cancer (TNBC) tumors over the parent siRNA. This structure achieves approximately 80% silencing of the anti-apoptotic oncogene MCL1 and yields better survival outcomes in three TNBC models than an MCL-1 small molecule inhibitor. These studies provide new structure-function insights on siRNA-lipid conjugate structures that are intravenously injected, associate in situ with serum albumin, and improve pharmacokinetics and tumor treatment efficacy.