Ultrasound-Remote Selected Activation Mitophagy for Precise Treatment of Rheumatoid Arthritis by Two-Dimensional Piezoelectric Nanosheets

Excess reactive oxygen species (ROS) produced by abnormal mitochondria is one of the critical triggers of rheumatoid arthritis (RA). Existing nanocatalytic therapies can only catalyze the breakdown of ROS but cannot address the root cause of ROS production, i.e., abnormal mitochondria. Here, we designed an ultrasound (US) piezoelectric catalytic therapy, which can induce mitophagy in a spatiotemporally controlled manner to treat RA. The prepared two-dimensional piezoelectric nanosheets (NSs) Fe/BiOCl with US catalytic activity can efficiently generate electrons under US stimulation to meet the purpose of consuming H⁺ in the outer mitochondrial membrane and disturbing the H⁺ supply in the mitochondrial matrix. This causes depolarization of the mitochondrial membrane potential (MMP), triggering the autophagy of mitochondria in regions of inflammation to eliminate the source of ROS regeneration. Analysis of cellular and RA model-related experiments showed that piezoelectric US-catalyzed therapy involving Fe/BiOCl NSs alleviated RA by inducing mitophagy. This provides an explanation of the mechanism for piezoelectric US catalytic therapy and suggests promising strategies for biomedical applications of US piezoelectric materials.