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A ROS-responsive microsphere capsule encapsulated with NADPH oxidase 4 inhibitor ameliorates macrophage inflammation
Jinze Zhen1, Tianhao Wan1, Guangxin Sun2
1Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai, 200011, China.
Abstract:
Inflammatory macrophages within the synovium play a pivotal role in the progression of arthritis inflammation. Effective drug therapy targeting inflammatory macrophages has long been a goal for clinicians and researchers. The standard approach for treating osteoarthritis (OA) involves systemic treatment and local injection. However, the high incidence of side effects associated with long-term drug administration increases the risk of complications in patients. Additionally, the rapid clearance of the joint cavity poses a biological barrier to the therapeutic effect. NADPH oxidase 4 (NOX4) is an enzyme protein regulating the cellular redox state by generating reactive oxygen species (ROS) within the cell. In this study, we designed and fabricated a hydrogel microsphere consisting of methyl methacrylate (MMA) and polyvinyl acetate (PVA) as the outer layer structure. We then loaded GLX351322 (GLX), a novel selective NOX4 inhibitor, into hydrogel microspheres through self-assembly with the compound polyethylene glycol ketone mercaptan (mPEG-TK) containing a disulfide bond, forming nanoparticles (mPEG-TK-GLX), thus creating a two-layer drug-loaded microspheres capsule with ROS-responsive and slow-releasing capabilities. Our results demonstrate that mPEG-TK-GLX@PVA-MMA effectively suppressed TBHP-induced inflammation, ROS production, and ferroptosis, indicating a promising curative strategy for OA and other inflammatory diseases in the future.
Insights
This study developed novel nanoparticles to treat arthritis inflammation by targeting inflammatory macrophages. The new drug delivery system effectively reduced inflammation and oxidative stress, offering a promising new therapy for osteoarthritis.
Area of Science:
- Biomedical Engineering
- Drug Delivery Systems
- Inflammation Research
Background:
- Inflammatory macrophages in the synovium drive arthritis progression.
- Current osteoarthritis treatments face challenges like side effects and rapid drug clearance from joints.
- Targeting inflammatory pathways offers a therapeutic strategy for inflammatory diseases.
Purpose of the Study:
- To develop a novel drug delivery system for targeting inflammatory macrophages in arthritis.
- To create ROS-responsive and slow-releasing nanoparticles for enhanced therapeutic efficacy.
- To investigate the potential of NOX4 inhibition in treating inflammatory conditions like osteoarthritis.
Main Methods:
- Fabrication of a two-layer hydrogel microsphere capsule using methyl methacrylate (MMA) and polyvinyl acetate (PVA).
- Loading of a selective NADPH oxidase 4 (NOX4) inhibitor, GLX351322 (GLX), into nanoparticles via self-assembly with mPEG-TK.
- Evaluation of the nanoparticles' efficacy in suppressing inflammation, ROS production, and ferroptosis in a TBHP-induced model.
Main Results:
- The developed mPEG-TK-GLX@PVA-MMA nanoparticles demonstrated ROS-responsive and slow-release properties.
- The system effectively suppressed TBHP-induced inflammation and reactive oxygen species (ROS) production.
- The nanoparticles showed significant reduction in ferroptosis, indicating a potent anti-inflammatory effect.
Conclusions:
- The novel GLX-loaded nanoparticles represent a promising strategy for treating osteoarthritis and other inflammatory diseases.
- The ROS-responsive and slow-release characteristics enhance therapeutic potential by overcoming limitations of current treatments.
- Targeting NOX4 with this advanced drug delivery system offers a new avenue for managing inflammatory conditions.
