ABSTRACT Oxidative stress plays a key role in the pathogenesis of osteoarthritis (OA), contributing directly to tissue breakdown as well as to chronic pain. Attempts to boost antioxidant defenses in the joint have been clinically disappointing - conventional small molecules and exogenously delivered antioxidant enzymes are plagued by poor stability and bioavailability, as well as rapid joint clearance following intra-articular injections. To address these limitations, our parent R01 engineers manganese dioxide nanoparticles (MnO2 NPs), or “nanozymes”, that mimic the reactive oxygen species (ROS) scavenging functions of antioxidant enzymes, but have significant advantages in terms of stability, cost, and bioavailability. Indeed, we demonstrated the properties of these nanomaterials can be tailored for joint tissue retention and cell uptake, which is important for addressing critical barriers to therapeutic delivery in OA. The parent R01 focuses on optimizing the antioxidant activity of the MnO2 NPs, interrogating their chondroprotective and anti-inflammatory mechanisms in vitro, and evaluating their disease-modifying ability in vivo in a rodent model of PTOA. This supplement expands on these studies to include comprehensive evaluation of pain mechanisms in response to MnO2 NP treatment, with particular focus on neuropathic pain. OA patients can experience a combination of nociceptive and neuropathic pain. With nociceptive pain, tissue damage and inflammation leads to activation of nociceptors and pain transmission. Neuropathic pain, however, is caused by damage to the nerves themselves, which can occur with joint injury or as a result of structural changes in the joint as OA progresses. Treatment of neuropathic pain is challenging, as commonly used anti-inflammatories are ineffective, and therapeutic options are limited by risk of addiction and serious adverse effects. Oxidative stress in known to trigger and maintain neuropathic pain, by inducing damage and mitochondrial dysfunction in nerves. Given their pronounced antioxidant functions, stability, and bioavailability, we hypothesize that MnO2 NPs will be effective at alleviating neuropathic pain in PTOA. To lay the groundwork for this scientific direction, this supplement aims to characterize the antioxidant functions of MnO2 NPs with neural cells in vitro, and evaluate biomarkers for neuropathic pain in vivo in response to treatment with MnO2 NP in a PTOA model. These biomarkers, such as joint innervation patterns and cellular composition of the dorsal root ganglion, will complement the behavior analyses, biochemical analyses, and histopathologic analyses in the parent R01. This comprehensive assessment of OA pathogenesis, in terms of joint structure, function, and pain mechanisms, may facilitate successful preclinical to clinical translation of this or other antioxidant strategies for musculoskeletal diseases and chronic pain.