Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis
Open accessAbstract
Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases that are associated with pain and lost quality of life. No disease modifying OA drugs are currently available. RA treatments are better established but are not always effective and can cause immune suppression. Here, an MMP13-selective siRNA conjugate was developed that, when delivered intravenously, docks onto endogenous albumin and promotes preferential accumulation in articular cartilage and synovia of OA and RA joints. MMP13 expression was diminished upon intravenous delivery of MMP13 siRNA conjugates, consequently decreasing multiple histological and molecular markers of disease severity, while also reducing clinical manifestations such as swelling (RA) and joint pressure sensitivity (RA and OA). Importantly, MMP13 silencing provided more comprehensive OA treatment efficacy than standard of care (steroids) or experimental MMP inhibitors. These data demonstrate the utility of albumin ‘hitchhiking’ for drug delivery to arthritic joints, and establish the therapeutic utility of systemically delivered anti-MMP13 siRNA conjugates in OA and RA. Editorial summary: Lipophilic siRNA conjugates optimized for albumin binding and “hitchhiking” can be leveraged to achieve preferential delivery to and gene silencing activity within arthritic joints. Chemical stabilization of the lipophilic siRNA enables intravenous siRNA delivery without lipid or polymer encapsulation. Using siRNA sequences targeting MMP13, a key driver of arthritis-related inflammation, albumin hitchhiking siRNA diminished MMP13, inflammation, and manifestations of osteoarthritis and rheumatoid arthritis at molecular, histological, and clinical levels, consistently outperforming clinical standards of care and small molecule MMP antagonists.
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Prior studies showed no evidence of systemic toxicity induced by L2-siRNA after intravenous injection.
“Consistent with prior studies showing no evidence of systemic toxicity induced by L2-siRNA after intravenous injection,30,46 we similarly did not observe changes in serum markers after ICV injection (Supplementary Fig. 14).”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [46]
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Lallo, V. A., & Bracaglia, L. G. (2023) · Tissue Engineering Part A · doi:10.1089/ten.tea.2023.0296 · Cited by 9 · see citing works
The role of TRIM proteins in chronic inflammation-associated musculoskeletal diseases
Livshits, G., & Kalinkovich, A. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102837 · Cited by 5 · see citing works
A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine
Walton, B. L., Shattuck-Brandt, R. L., Hamann, C. A., Tung, V. W., Colazo, J. M., Brand, D. D., Hasty, K. A., Duvall, C. L., & Brunger, J. M. (2024) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2024.12.002 · Cited by 5 · see citing works
Self-citationSorets, A., Schwensen, K., Francini, N., Kjar, A., Abdulrahman, A., Shostak, A., Katdare, K., Schoch, K., Cowell, R., Park, J., et al. (2024) · doi:10.1101/2024.06.09.598079 · Cited by 4 · see citing works
“Consistent with prior studies showing no evidence of systemic toxicity induced by L2-siRNA after intravenous injection, 30,46 we similarly did not observe changes in serum markers after ICV injection (Supplementary Fig.”
Self-citationTeaming up to overcome challenges toward translation of new therapeutics for osteoarthritis
Scanzello, C. R., Hasty, K. A., Chung, C. B., Griffin, T. M., Willett, N. J., Krug, H. E., Chu, C., Ewart, D. T., Jerban, S., Baker, J. F., et al. (2024) · Journal of Orthopaedic Research® · doi:10.1002/jor.25944 · Cited by 3 · see citing works
Self-citationSorets, A. G., Schwensen, K. R., Francini, N., Kjar, A., Lyons, S., Park, J. C., Palmer, D., Abdulrahman, A. M., Cowell, R. P., Katdare, K. A., et al. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114226 · Cited by 2 · see citing works
Self-citationGhidini, A., & Singh, A. (2023) · GEN Biotechnology · doi:10.1089/genbio.2023.0049
- Authors
- Colazo, J. M., Hoogenboezem, E. N., Keech, M. C., Francini, N., Shah, V., Yu, F., Lo, J. H., Sorets, A. G., McCune, J. T., Cho, H., DeJulius, C. R., Michell, D. L., Maerz, T., Vickers, K. C., Gibson-Corley, K. N., Hasty, K. A., Crofford, L., Cook, R. S., & Duvall, C. L.
- Affiliations
- Vanderbilt University (US)
- University of Tennessee Health Science Center (US)
- Vanderbilt University Medical Center (US)
- Corresponding author
- Duvall, Craig L.
- ORCID
- Colazo, Juan M.
- Hoogenboezem, Ella N.
- Keech, Megan C.
- Francini, Nora
- Shah, Veeraj
- Yu, Fang
- Lo, Justin H.
- Sorets, Alexander G.
- McCune, Joshua T.
- Cho, Hongsik
- DeJulius, Carlisle R.
- Michell, Danielle L.
- Maerz, Tristan
- Vickers, Kacey C.
- Gibson-Corley, Katherine N.
- Hasty, Karen A.
- Crofford, Leslie
- Cook, Rebecca S.
- Duvall, Craig L.
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2023-06-04
- PMC
- PMC10274717
- OpenAlex
- W4379374341
- Cited by
- 11
- References
- 84
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 4
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- U.S. Department of Defense (CDMRP OR130302, OR130302, DOD CDMRP OR130302)
- Rheumatology Research Foundation
- Vanderbilt University
- National Institutes of Health (1s10od023475-01a1, NIH-R01, CA-068485)
- Natural Sciences and Engineering Research Council of Canada
- National Cancer Institute (CA068485, S10OD023475, NIH R01 CA224241, R01CA224241, P30CA068485, R01CA260958)
- National Institute of General Medical Sciences (T32GM007347)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR078636)
- National Institute of Biomedical Imaging and Bioengineering (R01EB019409)
- National Center for Research Resources (S10RR027631)
- Congressionally Directed Medical Research Programs (DOD CDMRP OR130302, OR130302)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- siRNA conjugates, MMP-13, osteoarthritis, rheumatoid arthritis, carrier-free drug delivery, synovium, gene silencing, joint inflammation
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