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.
