A modular platform for targeted RNAi therapeutics
Abstract
Previous studies have identified relevant genes and signalling pathways that are hampered in human disorders as potential candidates for therapeutics. Developing nucleic acid-based tools to manipulate gene expression, such as short interfering RNAs 1-3 (siRNAs), opens up opportunities for personalized medicine. Yet, although major progress has been made in developing siRNA targeted delivery carriers, mainly by utilizing monoclonal antibodies (mAbs) for targeting 4-8, their clinical translation has not occurred. This is in part because of the massive development and production requirements and the high batch-to-batch variability of current technologies, which rely on chemical conjugation. Here we present a self-assembled modular platform that enables the construction of a theoretically unlimited repertoire of siRNA targeted carriers. The self-assembly of the platform is based on a membrane-anchored lipoprotein that is incorporated into siRNA-loaded lipid nanoparticles that interact with the antibody crystallizable fragment (Fc) domain. We show that a simple switch of eight different mAbs redirects the specific uptake of siRNAs by diverse leukocyte subsets in vivo. The therapeutic potential of the platform is demonstrated in an inflammatory bowel disease model by targeting colon macrophages to reduce inflammatory symptoms, and in a Mantle Cell Lymphoma xenograft model by targeting cancer cells to induce cell death and improve survival. This modular delivery platform represents a milestone in the development of precision medicine.
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The targeting strategy designed using the ASSET linker system is the first example of targeted CRISPR-Cas9 therapeutic gene editing for treating metastatic tumors.
“The targeting strategy we designed, using the ASSET linker system (22, 23), is, to our knowledge, the first example of targeted CRISPR-Cas9 therapeutic gene editing for treating metastatic tumors.”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [23]
Targeted LNPs can be administered systemically to target both localized and disseminated cells.
“Moreover, targeted LNPs can be administered systemically to target both localized and disseminated (such as metastatic and/or hematopoietic) cells (22, 23).”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [23]
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“Kedmi and colleagues overcame this issue by designing a modular platform, referred to as anchored secondary scFv enabling targeting or ASSET, which can incorporate any antibody onto the surface of an LNP (97).”
Background
- Authors
- Kedmi, R., Veiga, N., Ramishetti, S., Goldsmith, M., Rosenblum, D., Dammes, N., Hazan-Halevy, I., Nahary, L., Leviatan-Ben-Arye, S., Harlev, M., Behlke, M., Benhar, I., Lieberman, J., & Peer, D.
- Affiliations
- Tel Aviv University (IL)
- Integrated DNA Technologies (United States) (US)
- Boston Children's Hospital (US)
- Corresponding author
- Peer, Dan
- ORCID
- Venue
- Nature Nanotechnology
- Published
- 2018-01-29
- Volume
- 13
- Issue
- 3
- Pages
- 214-219
- ISSN
- 1748-3387 (ISSN-L)
- 1748-3395
- OpenAlex
- W2789720473
- Cited by
- 320
- References
- 19
- Citations by year
- 2026: 26 · 2025: 52 · 2024: 61 · 2023: 36 · 2022: 43 · 2021: 38 · 2020: 33 · 2019: 20 · 2018: 11
- FWCI
- 9.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Nanotechnology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Leona M. and Harry B. Helmsley Charitable Trust
- Tel Aviv University
- 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 › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- siRNA delivery, RNAi therapeutics, lipid nanoparticles, self-assembly, monoclonal antibodies, targeted delivery, inflammatory bowel disease, mantle cell lymphoma, personalized medicine, nucleic acid therapeutics
- MeSH terms
- RNAi Therapeutics, RAW 264.7 Cells, Animals, Antibodies, Monoclonal, Colitis, Female, Lipoproteins, Liposomes, Mice, Inbred C57BL, Drug Delivery Systems, RNA Interference, RNA, Small Interfering, Mice
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