Ultrasound-driven BaTiO ₃ nanorobots patching immunologic barrier to cure chronic rheumatoid arthritis

Abstract

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 BaTiO 3 (BTO) ultrasound-driven nanorobots (USNRs) by the solvothermal synthesis method, which demonstrates satisfactory electromechanical 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.

Electrical Stimulation for Immunomodulation

“…In another study, Jiang et al in 2023 developed piezoelectric BTO nanoparticles which can be activated by ultrasound for generating electrical stimulation for reprogramming the macrophage phenotype toward M2 for improving the pro-inflammatory conditions for the treatment of rheumatoid arthritis (RA). 86 The obtained results showed that electrical stimulation resulted in decreases in the levels of FAP-α and TNF-α which altered the macrophage phenotype from M1 to M2.…”

“…In addition, ultrasound activated piezoelectricity generation has also been utilized to tune macrophage behavior for the treatment of inflammatory diseases such as rheumatoid arthritis. , For instance, Li et al in 2023 stimulated piezoelectric nanosheets, Fe/BiOCl NSs, using ultrasound in an in vivo articular inflammation model to study its effect on macrophage polarization . From the results, it was observed that CD80+ macrophages decreased by 12.3% and CD206+ macrophages increased by 3.5%, suggesting a successful M2 polarization.…”

“…Upon US stimulation, Fe/BiOCl NSs generated the electrons which led to the consumption of H + in the mitochondrial membrane causing the depolarization of the mitochondrial membrane potential, hence induing mitophagy which contributes to the anti-inflammatory effect by polarizing the macrophages to the M2 phenotype. In another study, Jiang et al in 2023 developed piezoelectric BTO nanoparticles which can be activated by ultrasound for generating electrical stimulation for reprogramming the macrophage phenotype toward M2 for improving the pro-inflammatory conditions for the treatment of rheumatoid arthritis (RA) . The obtained results showed that electrical stimulation resulted in decreases in the levels of FAP-α and TNF-α which altered the macrophage phenotype from M1 to M2.…”

“…Recently, electrical stimulation has also been reported to promote macrophage phagocytosis for relieving the progression of rheumatoid arthritis (RA) by targeting the tissue resident macrophage (TRM) receptors. Jiang et al in 2023 employed ultrasound to trigger the piezoelectric tetragonal BaTiO 3 (BTO) for generating electric fields to stimulate the TRM barrier across the joints in a noninvasive manner . The ultrasound treatment generated negative charges on the surface of BTO which caused the binding between TREM2 TRM and BTO, patching the immunological barrier.…”

“…Jiang et al in 2023 employed ultrasound to trigger the piezoelectric tetragonal BaTiO 3 (BTO) for generating electric fields to stimulate the TRM barrier across the joints in a noninvasive manner. 86 The ultrasound treatment generated negative charges on the surface of BTO which caused the binding between TREM2 TRM and BTO, patching the immunological barrier. In another study, electric fields generated by 3D printed piezoelectric hydrogels consisting of ZnO nanoparticle modified PVDF/sodium alginate (SA) increased the expression of TNF-α for promoting neutrophil phagocytosis.…”