2. Academic Validation
  3. siRNA conjugate with high albumin affinity and degradation resistance for delivery and treatment of arthritis in mice and guinea pigs

siRNA conjugate with high albumin affinity and degradation resistance for delivery and treatment of arthritis in mice and guinea pigs

  • Nat Biomed Eng. 2025 May 16. doi: 10.1038/s41551-025-01376-x.
Juan M Colazo 1 2 3,  Megan C Keech 2,  Veeraj Shah 2,  Ella N Hoogenboezem 2,  Justin H Lo 2 4 5,  Nora Francini 2,  Nina T Cassidy 2,  Fang Yu 2,  Alexander G Sorets 2,  Joshua T McCune 2,  Carlisle R DeJulius 2,  Hongsik Cho 6,  Danielle L Michell 4,  Tristan Maerz 7,  Kacey C Vickers 4,  Katherine N Gibson-Corley 8,  Karen A Hasty 6,  Leslie J Crofford 9,  Rebecca S Cook 2 5,  Craig L Duvall 10
Affiliations

Affiliations

  • 1 Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 2 Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
  • 3 Department of Orthopaedic Surgery, Washington University in St Louis, St Louis, MO, USA.
  • 4 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 5 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 6 Department of Orthopaedic Surgery and Biomedical Engineering, UTHSC, Memphis VA Medical Center, Memphis, TN, USA.
  • 7 Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.
  • 8 Department of Pathology, Microbiology, and Immunology, Division of Comparative Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 9 Department of Medicine, Division of Rheumatology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 10 Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA. craig.duvall@vanderbilt.edu.
PMID: 40379798 DOI: 10.1038/s41551-025-01376-x
Abstract

Osteoarthritis and rheumatoid arthritis are debilitating joint diseases marked by pain, inflammation and cartilage destruction. Current osteoarthritis treatments only relieve symptoms, while rheumatoid arthritis therapies can cause immune suppression and provide variable efficacy. Here we developed an optimized small interfering RNA targeting matrix metalloproteinase 13 for preferential delivery to arthritic joints. Chemical modifications in a stabilizing 'zipper' pattern improved RNA resistance to degradation, and two independent linkers with 18 ethylene glycol repeats connecting to tandem C18 lipids enhanced albumin binding and targeted delivery to inflamed joints following intravenous administration. In preclinical models of post-traumatic osteoarthritis and rheumatoid arthritis, a single intravenous injection of the albumin-binding small interfering RNA achieved long-term joint retention, sustained gene silencing and reduced matrix metalloproteinase 13 activity over 30 days, resulting in decreased cartilage erosion and improved clinical outcomes, including reduced joint swelling and pressure sensitivity. This approach demonstrated superior efficacy over corticosteroids and small-molecule MMP inhibitors, highlighting the therapeutic promise of albumin 'hitchhiking' for targeted, systemic delivery of gene-silencing therapeutics to treat osteoarthritis and rheumatoid arthritis.

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