Oral Biosurfactant-Stabilized, ROS-Responsive Nanocarriers Demonstrate Targeted Anti-Arthritic Efficacy and Cytokine Modulation in Collagen-Induced Arthritis Models

Objective: This study aimed to develop and evaluate sophorolipid-stabilized, thioketal-gated nanostructured lipid carriers (SL-NLCs) for oral delivery of celecoxib with reactive oxygen species (ROS)-responsive drug release, improved bioavailability, and joint-targeted therapeutic efficacy in collagen-induced arthritis (CIA) models. Methods: SL-NLCs were formulated using a microfluidic ethanol injection method incorporating a thioketal (TK-PEG-Chol) linker to achieve ROS sensitivity. Physicochemical characterization, mucus penetration, and Caco-2 transport studies were performed, along with in vitro anti-inflammatory evaluation, pharmacokinetic analysis, and in vivo therapeutic assessment in CIA rats. Results: The optimized SL-NLCs exhibited uniform spherical morphology, high encapsulation efficiency (>91%), and ROS-triggered accelerated drug release. Enhanced mucosal diffusivity (0.85 µm²/s) and approximately 5.2-fold higher epithelial permeability (Papp) were observed compared to the free drug. The SL-NLC(TK) formulation improved oral bioavailability of celecoxib by approximately 3.5-fold and demonstrated preferential accumulation in synovial tissue. Significant reductions in TNF-α, IL-6, and oxidative stress markers were observed, along with restoration of antioxidant enzyme levels. Joint protection and tissue recovery were confirmed through micro-CT and histological analysis. Conclusion: Sophorolipid-stabilized, thioketal-gated nanocarriers significantly enhance oral bioavailability, enable ROS-responsive drug release, and provide targeted anti-arthritic effects, demonstrating a sustainable and translational nanomedicine platform for rheumatoid arthritis therapy.