Manganese dioxide as a nanozyme to mitigate oxidative stress in osteoarthritis

项目总结 在这项建议中，我们的目标是表征一个多酶和软骨保护功能。 生物活性生物材料二氧化锰(MnO2)纳米颗粒(NPs)作为治疗策略 减轻骨关节炎(OA)的氧化应激。这项工作的动机是解决以下关键需求 将骨质疏松症视为迫在眉睫的公共卫生危机的局限性，预计到2010年将影响全球1.3亿人 2050年，由于人口老龄化。 氧化应激，即活性氧(ROS)生成和抗氧化剂之间的失衡 功能，已知有助于骨性关节炎的进展，并可能代表一个重要的治疗目标。那里 已经有大量研究评估抗氧化剂和小分子作为治疗剂的使用， 然而，这些疗法受到关节内生物利用度和稳定性差的限制。这样做的目的是 建议利用一种金属氧化物生物材料(MnO2)来克服保留和生物利用度的限制 并试图探索模拟酶的功能来减少氧化应激的影响。我们之前已经 表明MnO2可以被设计成具有软骨靶向特性，例如大小和电荷，这可以 克服传统抗氧化剂疗法的局限性。利用这些特性，我们已经看到了改进 MnO2纳米颗粒在健康关节和骨关节炎关节中的滞留。由于靶向软骨的障碍，这一进展是 对软骨保护疗法的发展至关重要。我们假设MnO2纳米粒子含有酶 模仿的特性将减少关节中的氧化压力，从而减轻疼痛和疾病 发病机制。 酶模拟功能的表征是纳米二氧化锰用于生物医学的关键 并可能进一步将这种生物材料归类为“纳米酶”。我们的实验室已经确定了 纳米二氧化锰对过氧化氢的清除作用及纳米酶分类 MnO2具有类过氧化氢酶、类超氧化物和类过氧化物酶的功能。在目标1中，我们将研究MnO2 NPs如何 影响隔室特定的过氧化氢的产生和氧化应激的下游效应。具体来说， 我们将表征纳米二氧化锰的抗氧化剂性质及其对氧化还原信号的影响。 保护软骨和发炎作用。在目标2中，我们将评估纳米二氧化锰对小鼠的治疗效果。 利用创伤后骨性关节炎(PTOA)啮齿动物模型，通过综合评估NP在 关节、关节重塑和行为。关节创伤后的立即治疗会导致PTOA，是一种 通过利用仍完好无损的软骨来翻译软骨靶向疗法的关键机会 可能对减轻氧化应激有反应。拟议的工作具有重大意义和创新性，揭示了 缓解氧化应激和促进酶模拟疗法的使用的关键机制 可能有助于翻译减缓关节疾病进展的策略。

PROJECT SUMMARY In this proposal, we aim to characterize the multi-enzymatic and chondroprotective functions of a bioactive biomaterial, manganese dioxide (MnO2) nanoparticles (NPs), as a therapeutic strategy to mitigate oxidative stress in osteoarthritis (OA). The motivation for this work is the critical need to address limitations for treating OA as a looming public health crisis, projected to affect 130 million people worldwide by 2050 due to an aging population. Oxidative stress, the imbalance between reactive oxygen species (ROS) generation and antioxidant function, is known to contribute to OA progression and may represent an important therapeutic target. There have been numerous studies to evaluate the use of antioxidants and small molecules as therapeutic agents, however these therapies are limited by poor bioavailability and stability within the joint. The objective of this proposal is to utilize a metal-oxide biomaterial (MnO2) to overcome limitations of retention and bioavailability and seeks to explore enzyme-mimicking functions to reduce the effects of oxidative stress. We have previously shown that MnO2 can be engineered with cartilage-targeting properties, such as size and charge, that can overcome limitations of traditional antioxidant therapies. Leveraging these properties we have seen improved retention of MnO2 NPs in healthy and OA joints. Due to the barriers for targeting cartilage, this advancement is critical in the development of a chondroprotective therapy. We hypothesize that MnO2 NPs possess enzyme mimicking properties that will reduce oxidative stress in the joint thereby alleviating pain and disease pathogenesis. Characterization of enzyme mimicking functions is critical in the use of MnO2 NPs for biomedical applications and may further classify the biomaterial as a ‘nanozyme.’ Our lab has already characterized the hydrogen peroxide scavenging properties of MnO2 NPs and we anticipate ‘nanozyme’ classification will outline catalase-like, superoxide-like, and peroxidase-like functions of MnO2. In Aim 1, we will examine how MnO2 NPs influence compartment specific H2O2 production and the downstream effects of oxidative stress. Specifically, we will characterize the antioxidant-like properties of MnO2 NPs and their impact on redox signaling, chondroprotection, and inflammatory effects. In Aim 2 we will evaluate the therapeutic efficacy of MnO2 NPs in vivo using a rodent model of post traumatic OA (PTOA) through comprehensive evaluation of NP retention in the joint, joint remodeling, and behavior. Immediate treatment following joint trauma, which leads to PTOA, is a critical opportunity for translation of a cartilage targeting therapy by leveraging cartilage that is still intact and may be responsive to mitigating oxidative stress. The proposed work is significant and innovative by revealing key mechanisms for mitigating oxidative stress and advancing the use of an enzyme-mimicking therapy that may facilitate translation of strategies to slow the progression of joint disease.