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Abstract Gene therapy has the potential to facilitate targeted expression of therapeutic proteins to promote cartilage regeneration in osteoarthritis (OA). The dense, avascular, aggrecan‐glycosaminoglycan (GAG) rich negatively charged cartilage, however, hinders their transport to reach chondrocytes in effective doses. While viral vector mediated gene delivery has shown promise, concerns over immunogenicity and tumorigenic side‐effects persist. To address these issues, this study develops surface‐modified cartilage‐targeting exosomes as non‐viral carriers for gene therapy. Charge‐reversed cationic exosomes are engineered for mRNA delivery by anchoring cartilage targeting optimally charged arginine‐rich cationic motifs into the anionic exosome bilayer by using buffer pH as a charge‐reversal switch. Cationic exosomes penetrated through the full‐thickness of early‐stage arthritic human cartilage owing to weak‐reversible ionic binding with GAGs and efficiently delivered the encapsulated eGFP mRNA to chondrocytes residing in tissue deep layers, while unmodified anionic exosomes do not. When intra‐articularly injected into destabilized medial meniscus mice knees with early‐stage OA, mRNA loaded charge‐reversed exosomes overcame joint clearance and rapidly penetrated into cartilage, creating an intra‐tissue depot and efficiently expressing eGFP; native exosomes remained unsuccessful. Cationic exosomes thus hold strong translational potential as a platform technology for cartilage‐targeted non‐viral delivery of any relevant mRNA targets for OA treatment.
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This content will become publicly available on March 1, 2027
Dose‐Dependent, Biomechanical Recovery of Permeability Ex Vivo in GAG‐Depleted Cartilage With a Synthetic Polyelectrolyte, Polystyrene Sulfonate
ABSTRACT Articular cartilage is a specialized connective tissue responsible for load‐bearing function in diarthrodial joints. In early osteoarthritis (OA), depletion of negatively charged glycosaminoglycans (GAGs) side chains within cartilage reduces its ability to maintain high osmotic pressure, leaving the matrix susceptible to further damage. In the biomechanical recovery of damaged cartilage, some OA therapies have focused on collagen repair to restore tissue stiffness, but comparatively fewer have targeted the osmotic contribution of GAGs to cartilage mechanics. In this study, we have investigated poly(styrene) sulfonate (PSS) as a synthetic proteoglycan mimic to restore lost negative charge in GAG‐depleted cartilage. Notably, PSS treatment led to near complete recovery of tissue permeability, a direct measure of fixed charge density. In contrast, other commercially available treatments tested did not show measurable biomechanical improvements. These findings, combined with tissue cytotoxicity experiments, demonstrate that PSS‐based molecules as synthetic GAG replacements are effective in restoring lost fixed charge density (FCD) and subsequent biomechanical properties of cartilage, thus supporting the potential of PSS as a novel therapeutic strategy for OA.
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- Award ID(s):
- 2237888
- PAR ID:
- 10691339
- Publisher / Repository:
- Wiley
- Date Published:
- Journal Name:
- Journal of Orthopaedic Research
- Volume:
- 44
- Issue:
- 3
- ISSN:
- 0736-0266
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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