PreprintCited by 11RNA Interference and Gene DeliveryOsteoarthritis Treatment and MechanismsNanoparticle-Based Drug Delivery

Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis

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Colazo, Juan M., Hoogenboezem, Ella N., Keech, Megan C., Francini, Nora, Shah, Veeraj, Yu, Fang, Lo, Justin H., Sorets, Alexander G. +11 more·2023·bioRxiv (Cold Spring Harbor Laboratory)

Abstract

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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Crossref · 10.1101/2023.05.31.542971

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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.
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-06-04
OpenAlex
W4379374341
Cited by
11
References
84
Citations by year
2025: 3 · 2024: 4 · 2023: 4
Type
posted content
Language
en
Open access
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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