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Cartilage targeting therapy with reactive oxygen species-responsive nanocarrier for osteoarthritis
Zengxin Jiang1,2, Hao Wang3, Zeng Zhang1,2
1Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Abstract:
Targeting cartilage is a promising strategy for the treatment of osteoarthritis, and various delivery vehicles were developed to assist the therapeutic agents into cartilage. However, the underlying biomechanisms and potential bioactivities remain oversimplified. Inspired by oxidative stress in the pathogenesis of osteoarthritis, we firstly testified the antioxidant capacity of a synthetic small molecule compound, oltipraz (OL), to the chondrocytes treated by IL-1β. Then a functional reactive oxygen species (ROS) responsive nanocarrier, mesoporous silica nanoparticles (MSN) modified with methoxy polyethylene glycol-thioketal, was constructed. In vitro biomolecular results showed that compared with OL alone, MSN-OL could significantly activate Nrf2/HO-1 signaling pathway, which exhibited better ROS-scavenging proficiency and greater anti-apoptotic ability to protect mitochondrial membrane potential of chondrocytes. Further bioinformatics analysis revealed that MSN-OL suppressed clusters of genes associated with extracellular matrix organization, cell apoptosis and cellular response to oxidative stress. Animal experiments further confirmed the great cartilage-protecting ability of MSN-OL through upregulating the expression of Nrf2/HO-1 signaling pathway without obvious toxicity. In summary, this study provided a delivery system through ROS-responsive regulation of the therapeutic agents into chondrocytes of the cartilage, and confirmed the exact biological mechanisms of this innovative strategy.
Insights
This study developed a novel nanocarrier (MSN-OL) to deliver oltipraz (OL) for osteoarthritis treatment. The nanocarrier effectively scavenges reactive oxygen species (ROS), protects cartilage cells, and shows therapeutic potential.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Osteoarthritis Research
Background:
- Osteoarthritis (OA) pathogenesis involves oxidative stress.
- Current cartilage-targeting delivery systems for OA lack detailed mechanistic understanding.
- Oltipraz (OL) shows antioxidant potential but requires effective delivery.
Purpose of the Study:
- To develop and evaluate a reactive oxygen species (ROS)-responsive nanocarrier for oltipraz (OL) delivery to cartilage.
- To elucidate the biomechanisms and bioactivities of the novel nanocarrier system in OA treatment.
- To assess the cartilage-protecting efficacy and safety of the developed nanocarrier in vitro and in vivo.
Main Methods:
- Constructed a ROS-responsive mesoporous silica nanoparticle (MSN) carrier modified with methoxy polyethylene glycol-thioketal, loaded with oltipraz (OL).
- Evaluated in vitro antioxidant capacity, Nrf2/HO-1 pathway activation, ROS-scavenging, and anti-apoptotic effects on chondrocytes.
- Conducted bioinformatics analysis and animal experiments to confirm cartilage protection and assess toxicity.
Main Results:
- MSN-OL significantly activated the Nrf2/HO-1 signaling pathway in chondrocytes, outperforming OL alone.
- The nanocarrier demonstrated superior ROS-scavenging and anti-apoptotic effects, preserving mitochondrial membrane potential.
- Bioinformatics and animal studies confirmed MSN-OL's cartilage-protecting ability via Nrf2/HO-1 upregulation without significant toxicity.
Conclusions:
- A novel ROS-responsive nanocarrier (MSN-OL) was successfully developed for targeted delivery of oltipraz in osteoarthritis.
- The system effectively regulates therapeutic agent delivery into chondrocytes, modulating oxidative stress and apoptosis.
- This strategy offers a promising approach for osteoarthritis treatment by elucidating specific biological mechanisms.
