Microfluidics-Enabled Nanoparticle for Multiscale Synergetic Osteoarthritis Therapy.

Osteoarthritis (OA) is a complex degenerative joint disease perpetuated by a vicious cycle of biomechanical, biochemical, and chondrocyte homeostasis imbalances, ultimately leading to progressive cartilage degradation. A simultaneous approach to biomechanical disturbances, chondrocyte metabolic imbalances, and maintaining cartilage homeostasis simultaneously holds promise in tackling this challenge. Herein, we report a microfluidics-enabled nanoparticle, termed ZCMC, formed by grafting a magnesium-modified chondroitin sulfate polymer layer onto a zein core preloaded with cannabidiol (CBD), for multiscale synergistic OA therapy. ZCMC achieved enhanced lubrication, reducing OA cartilage friction to levels akin to healthy cartilage. The sustained release of CBD and magnesium ions exerted anti-inflammatory and analgesic effects alongside the regulation of autophagy and inhibition of chondrocyte aging. The in vitro and in vivo experiments highlighted ZCMC's ability to enhance cartilage protection and matrix preservation, reduce inflammatory cytokines, improve gait function, mitigate joint damage, and prevent peripheral nerve demyelination. Transcriptome analysis revealed that ZCMC downregulates SCN9A expression in chondrocytes, inhibiting the Nav1.7 channel to maintain cellular homeostasis and facilitate cartilage repair. Preclinical evaluation in human OA cartilage explants further demonstrated ZCMC's efficacy in inhibiting explant degradation, restoring the mechanical properties of chondrocytes by modulating the Nav1.7 channel, and thereby facilitating the recovery of their normal biological behavior, ultimately inhibiting OA progression. By targeting multiple pathological aspects simultaneously, ZCMC nanoparticles may offer a promising translational strategy for treating OA.