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Cited by 52RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryRNA and protein synthesis mechanisms

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

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Hoogenboezem, Ella N., Patel, Shrusti S., Lo, Justin H., Cavnar, Ashley B., Babb, Lauren M., Francini, Nora, Gbur, Eva F., Patil, Prarthana +14 more·2024·Nature Communications
DOI 10.1038/s41467-024-45609-0PMC PMC10881965
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Abstract

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.

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Sorted by citations

Authors
Hoogenboezem, E. N., Patel, S. S., Lo, J. H., Cavnar, A. B., Babb, L. M., Francini, N., Gbur, E. F., Patil, P., Colazo, J. M., Michell, D. L., Sanchez, V. M., McCune, J. T., Ma, J., DeJulius, C. R., Lee, L. H., Rosch, J. C., Allen, R. M., Stokes, L. D., Hill, J. L., Vickers, K. C., Cook, R. S., & Duvall, C. L.
Affiliations
  • Vanderbilt University (US)
  • Vanderbilt University Medical Center (US)
Corresponding author
Duvall, Craig L.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-02-21
Volume
15
Issue
1
Pages
1581-1581
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-45609-0
PMC
PMC10881965
OpenAlex
W4392004456
Cited by
52
References
7
Citations by year
2026: 22 · 2025: 24 · 2024: 6
FWCI
7.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (R01 CA224241, R01 EB019409, R01 CA260958, R21 AR078636, T32 CA217834, F32 CA268705)
  • National Science Foundation (BMAT 1349604)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
siRNA conjugates, albumin binding, Mcl-1, triple-negative breast cancer, pharmacokinetics, intracellular delivery, RNA interference, intravenous injection
MeSH terms
Albumins, Antineoplastic Agents, Humans, Lipids, Gene Silencing, RNA, Small Interfering, Cell Line, Tumor, Myeloid Cell Leukemia Sequence 1 Protein, Triple Negative Breast Neoplasms

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