Objectives Despite preclinical studies involving miRNA therapeutics conducted in osteoarthritis (OA) over the years, none of these miRNAs have yet translated to clinical applications, owing largely to the lack of efficient intra-articular (IA) delivery systems. Here, we investigated therapeutic efficacy of the chondrocyte-specific aptamer-decorated PEGylated polyamidoamine nanoparticles (NPs)-based miRNAs delivery for OA.
Methods The role of miR-141/200c cluster during skeletal and OA development was examined by miR-141/200cflox/flox mice and Col2a1-CreERT2; miR-141/200cflox/flox mice. Histological analysis was performed in mouse joints and human cartilage specimens. Chondrocyte-specific aptamer-decorated NPs was designed, and its penetration, stability and safety were evaluated. OA progression was assessed by micro-CT analysis, X-ray and Osteoarthritis Research Society International scores after destabilising the medial meniscus surgery with miR-141/200c manipulation by NPs IA injection. Mass spectrometry analysis, molecular docking and molecular dynamics simulations were performed to investigate the interaction between aptamer and receptor.
Results Increased retention of NPs inside joint space is observed. The NPs are freely and deeply penetrant to mice and human cartilage, and unexpectedly persist in chondrocytes for at least 5 weeks. OA chondrocytes microenviroment improves endo/lysosomal escape of microRNAs (miRNAs). Therapeutically, IA injection of miR-141/200c inhibitors provides strong chondroprotection, whereas ectopic expression of miR-141/200c exacerbates OA. Mechanistically, miR-141/200c promotes OA by targeting SIRT1, which acetylates histone in the promoters of interleukin 6 (IL-6), thereby activating IL-6/STAT3 pathway.
Conclusions Our findings indicate that this nanocarrier can optimise the transport kinetics of miR-141/200c into chondrocytes, fostering miRNA-specific disease-modifying OA drugs development.
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Handling editor Josef S Smolen
Contributors All authors were involved in drafting or critically revising the manuscript for important intellectual content, and all authors approved the final version for publication. JL, XTW, M-LJ and HJ conceived the ideas and designed the experiments. M-LJ, FW, RG, LKY, YCL and JHX conducted experiments and analySed the data. JL and M-LJ interpreted the data and wrote the manuscript.
Funding This work is supported by The National Science Foundation of of China (No. 81972105, No. 81672159 and No. 81860406), and the Fundamental Research Funds for the Central Universities (No. 2242019K3DZ05).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Protocol approved by the ethical committee of Zhongda Hospital, Southeast University.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request.
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