Celecoxib-Loaded “Nano-in-Nano” Hierarchical Delivery System: Structure-Driven Synergistic Optimization of Diffusion Efficiency and Mechanical Stability for Osteoarthritis Therapy

Chuangzan Yang,1,2 Huashen He,1– 3 Yichao Li,1– 3 Sa Huang,1– 3 Yingneng Zhang,1,2 Weixin Xiao,1– 3 Zhixuan Peng,1,2 Xueyuan Luo,1,2 Shuohan Jiang,1,2 Yu Li,1,2 Liran Cen,1,2 Huanhuan Jia,4 Ying Liu,5 Junfeng Ban1– 3 1Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 2Engineering Research Center of Small Molecule Drugs Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Pharmaceutical Preparations Research and Evaluation, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 4Medical Devices Research & Testing Center, South China University of Technology, Guangzhou, People’s Republic of China; 5Graduate School, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of ChinaCorrespondence: Huanhuan Jia, Medical Devices Research & Testing Center, South China University of Technology, Guangzhou, Guangdong, 51006, People’s Republic of China, Email jiahuanhuan@scut.edu.cn Junfeng Ban, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 51006, People’s Republic of China, Email banjunfeng@163.comPurpose: Osteoarthritis (OA) joints present abnormal mechanical environments that limit drug retention and therapeutic efficacy. Current intra-articular systems cannot provide both sustained anti-inflammatory delivery and mechanical support. A celecoxib (CXB)-loaded “Nano-in-Nano” Hierarchical Delivery System (NiN-HDS) was developed to simultaneously optimize drug release and joint reinforcement.Methods: In this study, celecoxib-loaded PLGA nanoparticles (CXB-NPs) were prepared by emulsion solvent evaporation and incorporated into an electrospun nanofiber membrane combined with a genipin-crosslinked gelatin layer to form NiN-HDS. The system was characterized for particle size, zeta potential, porosity, hydrophilicity, swelling, degradation, mechanical properties, and in vitro CXB release. Therapeutic potential was evaluated in a rat OA model using histological and immunohistochemical analyses of cartilage and inflammatory markers.Results: NiN-HDS maintained nanoparticle stability, with CXB-NPs showing an average particle size of 138.4 ± 4.3 nm and a zeta potential of – 58.74 ± 16.58 mV. The system exhibited high porosity (87.16 ± 0.75%) and hydrophilicity (contact angle < 90°), achieved swelling equilibrium at 150 ± 10 min with a swelling ratio of 163.97 ± 9.76%, and degraded over 10 days with 88.53 ± 2.03% mass loss. Mechanical testing demonstrated high strength (Young’s modulus 17.24 ± 2.65 MPa, elongation at break 307.48 ± 32.01%. NiN-HDS provided sustained CXB release over 7 days, reaching 67.16% cumulative release. In vivo, it reduced cartilage damage and suppressed IL-1β and MMP-13 expression, while maintaining mechanical support and controlled drug delivery.Conclusion: In conclusion, we successfully developed NiN-HDS. Our results show that NiN-HDS combines sustained drug delivery with mechanical support, improves cartilage preservation and reduces local inflammation in a rat OA model, indicating that it can serve as a promising strategy for intra-articular therapy of osteoarthritis. This QR code provides access to a video abstract of the article. When scanned with a smartphone or QR code reader, it directs viewers to a short video presentation that summarizes the study.QR code linking to video abstract summarizing the study.Keywords: osteoarthritis, nanoparticles, electrospinning, drug delivery, mechanical support