Bioactive vitamin E-NAD+ conjugate nanoparticles for osteoarthritis management via simultaneous suppression of inflammation and oxidative stress.

The involvement of oxidative stress, inflammation, and energy metabolism disorders in osteoarthritis (OA) makes it challenging to handle these problems using a single therapeutic agent concurrently. Here, we report a tailored bioactive conjugate consisting of a hydrophobic radical-trapping antioxidant (vitamin E, VE), a hydrophilic nicotinamide adenine dinucleotide (NAD+), and a reactive oxygen species (ROS)-responsive phenylboronic acid linker. The conjugate self-assembly produced VE-NAD+ nanoparticles with high drug loading (>90%), a small hydrodynamic size (ca. 60 nm), and good kinetic stability. The nanoparticles significantly increased intracellular NAD+ levels, inhibited lipid peroxidation and oxidative stress, and suppressed pro-inflammatory cytokine release in macrophages (RAW 264.7) and rat chondrocytes in vitro. The multifunctional nanoparticles also down-regulated the key matrix metalloproteinases. Upon intra-articular delivery, the VE-NAD+ nanoparticles potently mitigated synovial inflammation and alleviated cartilage damage in a spontaneous OA mouse model, as evidenced by magnetic resonance imaging, histological staining, critical biomarker quantification, and OA grading assessment. This work provides an innovative disease-modifying approach to OA management, which may have applications in other aging-related disorders.