Cartilage-targeting exosomes for delivery of receptor antagonist of interleukin-1 in osteoarthritis treatment

Objective Exosomes are nano-sized cell-secreted vesicles naturally involved in joint tissue crosstalk and hold promise as drug carriers. Their negatively charged lipid bilayer, however, results in electrostatic repulsion from the anionic cartilage matrix limiting their applications in tissue targeting and drug delivery. Here we engineer cartilage targeting exosomes by reversing their net surface charge and use them for sustained delivery of interleukin-1 receptor antagonist (IL-1RA), a disease-modifying osteoarthritis (OA) drug that suffers from rapid joint clearance and poor cartilage uptake. Design Exosomes were surface modified by anchoring optimally charged cartilage targeting cationic motifs, Avidin (Av) and arginine-rich cationic peptide carrier (CPC). IL-1RA was surface anchored and encapsulated within the exosomes, creating two formulations: Exo Av -IL-1RA and Exo CPC -IL-1RA. Their penetration and retention in healthy and early OA cartilage were evaluated and compared with unmodified exosomes. The efficacy of Exo Av -IL-1RA and Exo CPC -IL-1RA in suppressing IL-1-induced tissue catabolism was tested using IL-1α challenged bovine cartilage explants over an 8-day culture period with a single dose and compared with free IL-1RA. Results Exo Av -IL-1RA and Exo CPC -IL-1RA, penetrated and retained in the full-thickness of early-stage arthritic cartilage explants. Free IL-1RA failed to suppress IL-1α-induced catabolism over the culture period. In contrast, Exo CPC -IL-1RA significantly suppressed cytokine-induced glycosaminoglycan loss and nitrite release, enhancing cell metabolism and viability with only a one-time dose. Conclusion Cartilage targeting charge-reversed CPC anchored exosomes successfully targeted and delivered IL-1RA to early-stage arthritic cartilage. They hold promise as a cell-free intra-cartilage depot-forming carrier for sustained delivery of OA biologics.