The disruption and reconstruction of the TREM2+ tissue resident macrophage (TRM) barrier on the surface of synovial lining play a key role in the activation and "remission" of rheumatoid arthritis (RA), which engender the prediction of this immunologic barrier as a potential driver for the achievement of "cure" in RA. However, strategies to promote the reconstruction of this barrier have not been reported, and the effect of patching this barrier remains unidentified. On the other hand, appropriate piezoelectric stimulation can reprogram macrophages, which has never been exerted on this barrier TRM yet. Herein, we design piezoelectric tetragonal BaTiO3 (BTO) ultrasound-driven nanorobots (USNRs) by the solvothermal synthesis method, which demonstrates satisfactory electro-mechanical conversion effects, paving the way to generate controllable electrical stimulation under ultrasound to reprogram the barrier TRM by minimally invasive injection into joint cavity. It is demonstrated that the immunologic barrier could be patched by this USNR effectively, thereby eliminating the hyperplasia of vessels and nerves (HVN) and synovitis. Additionally, TREM2 deficiency serum-transfected arthritis (STA) mice models are applied and proved the indispensable role of TREM2 in RA curing mediated by USNR. In all, our work is an interesting and important exploration to expand the classical tetragonal BTO nanoparticles in the treatment of autoimmune diseases, providing a new idea and direction for the biomedical application of piezoelectric ceramics.
The authors would like to acknowledge the assistance of Yanli Zhang, Imaging Core Facility, Technology Center for Protein Sciences, Tsinghua University, for the assistance of using the spinning disk confocal microscopy (Dragonfly, Andor); Yue Sun, Center of Biomedical Analysis, Tsinghua University, for the assistance of using the automatic digital slide scanning system (Axio Scan. Z1, Zeiss); Jingjing Wang, Center of Biomedical Analysis, Tsinghua University, for the assistance of using the microscopy slide scanner (Pannoramic SCAN, 3D HISTECH); Prof. Christophe Benoist, Harvard University, for his generous donation of KRN mice; and Prof. Xin Lin, Department of Immunology, Tsinghua University, for his generous donation of TREM2 KO mice.
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