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Dual-modal antioxidant and epigenetic synergy attenuates the self-perpetuating senescence cycle in osteoarthritis
Xueying An1,2,3, Hantao Cai1,2, Wenshu Wu1,2
1Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, 210008, China.
Abstract:
Osteoarthritis (OA) arises from chondrocyte senescence driven by intertwined oxidative stress and abnormal m6A methylation, with few treatments targeting both pathological pathways. Lycopene, an antioxidant, is limited by poor bioavailability, whereas Wilms tumor 1-associating protein (WTAP), a core m6A methyltransferase, has no specific inhibitors. Herein, we fabricated cartilage-targeted HPcLW nanoparticles (∼250 nm) via electrostatic self-assembly of human serum albumin (HSA) and poly-L-lysine (PLL) with collagen II-binding peptide, co-loaded with lycopene and WTAP siRNA. The targeting modification extended joint fluorescence retention to 10 days after intra-articular injection with good serum stability and biosafety. In aged mice and medial meniscus (DMM)-induced OA mouse models, intra-articular HPcLW attenuated cartilage degeneration, restored COL2 expression, and suppressed MMP13 levels. Mechanistically, WTAP siRNA suppressed m6A modification to downregulate PAI-1 expression, while lycopene scavenged ROS and protected siRNA integrity, cooperatively disrupting the WTAP/PAI-1 axis and alleviating mitochondrial dysfunction. By integrating antioxidant and epigenetic strategies, HPcLW counteracts the senescence loop, establishing the WTAP/PAI-1 axis as a therapeutic target and highlighting co-delivery nanomedicine for age-related joint diseases.
Insights
New nanoparticles deliver lycopene and WTAP siRNA to joints, effectively treating osteoarthritis by targeting oxidative stress and abnormal m6A methylation, offering a novel therapy for age-related joint diseases.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Osteoarthritis Research
Background:
- Osteoarthritis (OA) pathogenesis involves chondrocyte senescence, driven by oxidative stress and aberrant m6A methylation.
- Current OA treatments lack agents targeting both oxidative stress and epigenetic dysregulation.
- Lycopene's antioxidant benefits are hindered by poor bioavailability; WTAP, a key m6A methyltransferase, lacks specific inhibitors.
Purpose of the Study:
- To develop cartilage-targeted nanoparticles (HPcLW) co-delivering lycopene and WTAP siRNA for OA treatment.
- To investigate the combined antioxidant and epigenetic therapeutic effects of HPcLW in OA models.
- To establish the WTAP/PAI-1 axis as a viable therapeutic target for age-related joint diseases.
Main Methods:
- Fabrication of collagen II-binding peptide-modified HPcLW nanoparticles via electrostatic self-assembly of HSA and PLL.
- Co-loading of lycopene (antioxidant) and WTAP siRNA (epigenetic modulator) into the nanoparticles.
- Evaluation of nanoparticle targeting, retention, biosafety, and therapeutic efficacy in aged and DMM-induced OA mouse models.
Main Results:
- HPcLW nanoparticles demonstrated prolonged joint fluorescence retention (10 days) with good stability and biosafety.
- Intra-articular HPcLW administration attenuated cartilage degeneration, restored COL2 expression, and reduced MMP13 levels in OA models.
- HPcLW effectively suppressed the WTAP/PAI-1 axis, alleviated mitochondrial dysfunction, and counteracted chondrocyte senescence.
Conclusions:
- Co-delivery of lycopene and WTAP siRNA via HPcLW nanoparticles offers a synergistic approach to OA treatment.
- The study highlights the WTAP/PAI-1 axis as a critical therapeutic target in OA.
- HPcLW nanomedicine presents a promising strategy for managing age-related joint diseases by integrating antioxidant and epigenetic interventions.
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