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A Diselenide-Linkage Self-Assembled Nanoprodrug for Enhanced Osteoarthritis Treatment
Zhiyao Li1,2, Shanshan Yuan3, Chenchen Gong4
1School of Pharmacy, Anhui Medical University, Hefei 230032, P. R. China.
Abstract:
Osteoarthritis (OA), a prevalent degenerative joint disorder, is marked by chronic inflammation, oxidative stress, and cartilage degradation within a complex pathological microenvironment. Current monotherapies offer limited efficacy and fail to address the multifactorial nature of OA. To overcome these limitations, we developed a multifunctional self-assembling nanoprodrug W/KGN@DSeD nanoparticles (NPs) for precise and synergistic OA therapy. The system integrates a microenvironment-responsive diselenide-bridged prodrug (DSeD) of diclofenac (DIC) and the chondrogenic agent kartogenin (KGN), codelivered via nanoparticles modified with a cartilage-targeting peptide (WYRGRL). In the OA microenvironment, elevated ROS cleaves the diselenide bonds within DSeD, releasing DIC, KGN, and selenium (Se). The released Se activates the Nrf2 pathway, promoting antioxidant defense and protecting chondrocytes from oxidative stress. Concurrently, KGN promotes the production of ECM, facilitating cartilage regeneration and contributing to microenvironmental remodeling, while DIC mitigates inflammation and alleviates pain. In OA mouse models, W/KGN@DSeD NPs exhibit targeted cartilage accumulation, sustained retention, enhanced microenvironment modulation, and robust therapeutic efficacy. This ingenious diselenide-bond-based self-assembling nanoprodrug offers a promising strategy for microenvironment-adaptive, multimodal OA treatment.
Insights
A novel nanoparticle drug delivery system precisely targets osteoarthritis (OA) by releasing anti-inflammatory and cartilage-regenerating agents. This microenvironment-responsive therapy enhances antioxidant defense and promotes joint repair in OA models.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Drug Delivery Systems
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by inflammation, oxidative stress, and cartilage breakdown.
- Current OA treatments often lack efficacy due to the multifactorial nature of the disease and limitations of monotherapies.
Purpose of the Study:
- To develop a multifunctional, self-assembling nanoprodrug (W/KGN@DSeD nanoparticles) for precise and synergistic OA therapy.
- To engineer nanoparticles that respond to the OA microenvironment for targeted drug release and enhanced therapeutic outcomes.
Main Methods:
- Designed diselenide-bridged prodrugs (DSeD) of diclofenac (DIC) and kartogenin (KGN), encapsulated in nanoparticles.
- Modified nanoparticles with a cartilage-targeting peptide (WYRGRL) for enhanced accumulation.
- Evaluated nanoparticle performance in OA mouse models, assessing cartilage targeting, retention, and therapeutic efficacy.
Main Results:
- W/KGN@DSeD nanoparticles demonstrated targeted accumulation and sustained retention in cartilage.
- The nanoparticles effectively released DIC, KGN, and selenium (Se) in response to reactive oxygen species (ROS) in the OA microenvironment.
- Released Se activated the Nrf2 pathway, boosting antioxidant defense, while KGN promoted extracellular matrix (ECM) production for cartilage regeneration. DIC reduced inflammation and pain.
Conclusions:
- The developed diselenide-bond-based self-assembling nanoprodrug system offers a promising strategy for microenvironment-adaptive, multimodal OA treatment.
- This nanotechnology approach effectively addresses the complex pathology of OA, showing robust therapeutic efficacy in preclinical models.
