Saturday, May 17, 2025
5/17/2025
ROS scavenging nanoparticles for mitigating oxidative stress in osteoarthritis - PROJECT SUMMARY Oxidative stress plays a key role in the pathogenesis of osteoarthritis (OA) and is an important therapeutic target. While antioxidants or agents that target the reactive oxygen species (ROS) have been investigated for treating OA, many have demonstrated common disadvantages such as poor bioavailability and stability, as well as rapid joint clearance or release profiles from delivery vehicles following intra-articular injections. Therefore, there exists a critical need to localize and retain therapeutic levels of antioxidants within joint tissues for protection against the deleterious effects of oxidative stress. This proposal explores the application of manganese dioxide nanoparticles (MnO2 NPs) with antioxidant enzyme-like activity to reduce oxidative stress in OA joints while addressing limitations of small molecule antioxidants and natural enzymes, such as cost and stability. In addition, the properties of these nanomaterials can be tailored for tissue retention and cell targeting, which is important for addressing critical barriers to therapeutic localization and uptake in joint tissues. Recently, we reported engineering MnO2 NPs for uptake into cartilage and prolonged joint retention in vivo, as well as reduction of inflammation-induced oxidative stress in cartilage in vitro. Given its limited capacity to regenerate, cartilage is particularly vulnerable to oxidative stress and represents a crucial yet challenging tissue target. As such, this proposal focuses on interrogating the mechanisms of MnO2 NP-mediated chondroprotection while testing the efficacy of MnO2 NPs in an in vivo disease model. The central hypothesis is that MnO2 NPs will alleviate oxidative stress after joint injury and prevent or delay the onset of OA. In Aim 1, we will examine how uptake mechanisms and intracellular localization of MnO2 NPs affect compartment-specific ROS scavenging and the ability to rescue specific antioxidant pathways in chondrocytes. Furthermore, the effects of intracellular targeting versus extracellular retention on redox signaling, chondroprotective, and anti-inflammatory effects will be determined. In Aim 2, we will evaluate the effects of MnO2 NP treatment on oxidative stress and OA progression in vivo in a rat model of post-traumatic OA (PTOA). We will comprehensively evaluate the efficacy of the particles in modulating ROS in vivo, mitigating OA-related histological and biochemical (synovial fluid) changes, and alleviating OA-related pain and disability via behavioral assays. The proposed work will advance a new ROS scavenging strategy for the treatment of PTOA that overcomes persistent challenges with the delivery of antioxidants. The proposed work will also reveal key mechanisms involved in intracellular delivery to chondrocytes and how location and timing of antioxidant delivery impacts disease mechanisms. The mechanistic and comprehensive approach we propose here to characterize the effects of ROS scavenging by MnO2 NPs may facilitate successful translation long-term of this and/or other antioxidant strategies for joint injuries and disease.
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