Phospholipase A₂ inhibitor-loaded micellar nanoparticles attenuate inflammation and mitigate osteoarthritis progression.

Abstract

Treating osteoarthritis (OA) remains a major clinical challenge. Despite recent advances in drug discovery and development, no disease-modifying drug for knee OA has emerged with any notable clinical success, in part, due to the lack of valid and responsive therapeutic targets and poor drug delivery within knee joints. In this work, we show that the amount of secretory phospholipase A₂ (sPLA₂) enzyme increases in the articular cartilage in human and mouse OA cartilage tissues. We hypothesize that the inhibition of sPLA₂ activity may be an effective treatment strategy for OA. To develop an sPLA₂-responsive and nanoparticle (NP)-based interventional platform for OA management, we incorporated an sPLA₂ inhibitor (sPLA₂i) into the phospholipid membrane of micelles. The engineered sPLA₂i-loaded micellar NPs (sPLA₂i-NPs) were able to penetrate deep into the cartilage matrix, prolong retention in the joint space, and mitigate OA progression. These findings suggest that sPLA₂i-NPs can be promising therapeutic agents for OA treatment.