A Novel Endoplasmic Reticulum-Targeted Metal-Organic Framework-Confined Ruthenium (Ru) Nanozyme Regulation of Oxidative Stress for Central Post-Stroke Pain

Central post-stroke pain (CPSP) is a chronic neuropathic pain caused by cerebrovascular lesion or disfunction after stroke. Convincing evidence suggest that excessive reactive oxygen species (ROS), generated matrix metalloproteinase (MMPs) and neuroinflammation are largely involved in the development of pain. In this study, an effective strategy is reported for treating pain hypersensitivity using an endoplasmic reticulum (ER)-targeted metal-organic framework (MOF)-confined ruthenium (Ru) nanozyme. The Ru MOF is coated with a p-dodecylbenzene sulfonamide (p-DBSN) modified liposome with endoplasmic reticulum-targeted function. The experimental results reveals that ROS, Emmprin, MMP-2, and MMP-9 are upregulated in the brain of CPSP mice, along with the elevated expression of inflammation markers such as TNF-alpha and IL-6. Compared to vehicle, one-time intravenous administration of ER-Ru MOF significantly reduces mechanical hypersensitivity after CPSP for three days. Overall, ER-Ru MOF system can inhibit oxidative stress in the brain tissues of CPSP model, reduce MMPs expression, and suppress neuroinflammation response-induced injury, resulting in satisfactory prevention and effective treatment of CPSP during a hemorrhagic stroke. The ER-Ru MOF is expected to be useful for the treatment of neurological diseases associated with the vicious activation of ROS, based on the generality of the approach used in this study. An endoplasmic reticulum-targeted metal-organic framework-confined Ruthenium (Ru) nanozyme (ER-Ru MOF) with excellent catalase- and superoxide dismutase-like activity is designed. The ER-targeting nanozyme system exhibits enhanced CPSP relief ability through reducing the expression of TNF-a and IL-6, and inhibiting the activity of Emmprin, MMP-2, MMP-9.image