Precise Control of the in vivo Fate of Nanomicelles Efficiently Treats Advanced Rheumatoid Arthritis via EGFR/JNK/MMP9 Pathway

Na Jia,1 Yunzhen Gao,2 Lan Yang,3 Yani Xu,2 Zhirong Zhang,2 Jingwen Wang,1 Ling Zhang3,4 1Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China; 2Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Chengdu, 610041, People’s Republic of China; 3State Key Laboratory of Polymer Materials Engineering, College of Polymer Science and Engineering, Sichuan University, Chengdu, 610041, People’s Republic of China; 4West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Jingwen Wang, The Fourth Military Medical University, No. 127 Changle West Road, Xi’an, 710032, People’s Republic of China, Email [email protected] Ling Zhang, Sichuan University, No. 24 South Section 1, Yihuan Road, Chengdu, 610065, People’s Republic of China, Email [email protected]: Förster resonance energy transfer (FRET) technology is a tool for in vivo nanomedicine tracking. Nanomicelle-based drug carriers could improve therapeutic outcome for rheumatoid arthritis (RA). Self-assembled nanomicelles are a major type of them, and their drug-loading stability is seriously affected by the in vivo environment. Therefore, it is critical to understand the status of nanomicelles in vivo at different time points, in order to enable precise control of their dynamics to effectively deliver the drug to inflammatory joint.Methods: We applied FRET technology to elucidate the biofate of nanomicelles in an adjuvant induced arthritis (AIA) mice model and inflammatory larvae zebrafish models. We explored the molecular mechanism of swertiamarin-loaded nanomicelles (SWE-NMs) in improving RA symptoms through network pharmacology, molecular docking and immunofluorescence experiments.Results: Results showed that on cellular level the nanomicelles could enter inflammatory cells and completely release most cargoes in 12 h, while in animals, the majority of nanomicelles was destroyed within 72 h. Hence, we tailored an administration scheme for RA treatment. As expected, we loaded swertiamarin into the nanomicelles (SWE-NMs). The injection every 3 days (SWE-NMs/3) displayed enhanced accumulation in arthritic joints and strong anti-RA therapeutic effect, as well as good safety profile. In addition, network pharmacology, molecular docking analysis and immunofluorescence experiments revealed that SWE-NMs might work by blocking the epidermal growth factor receptor/c-Jun N-terminal kinase/matrix metalloproteinase (EGFR/JNK/MMP9) pathway.Conclusion: In summary, this study elucidated the biofate of nanomicelles with FRET technology in RA treatment, thus providing a basis for rationally improving administration scheme and giving clue for investigating other nano delivery systems. Keywords: nanomicelles, in vivo fate, Swertimarin, Förster resonance energy transfer, efficient treatment, advanced rheumatoid arthritis