Xiaohu Li, Fan Wang, Qianyi Li, Juan Wang, Ang Li, Honglei Xiao, Yida Chen, Yi Yu, Hongze Chang, Qin Zhang, Fangke Zhang, Xiaodong Liu, Wenguo Cui
ABSTRACT The inability of stochastic pharmacological interventions to precisely recalibrate aberrant mitochondrial membrane potential (MMP) poses a challenge to degenerated intervertebral disc tissue repair. Based on the biological rationale provided by clinical single‐cell RNA sequencing analysis, we developed an ultrasound‐activated piezo‐driven Fenton‐like system (Fe‐BTO) based microsphere (PF@MS). The US triggered piezopotential of the Fe‐BTO correlates with ultrasound‐associated iron valence modulation to mitigate catalytic bottlenecks linked to Fe 3 + /Fe 2 + interconversion, consuming local protons to upregulate MMP from pathological states to the physiological level. This process exhibits self‐limiting‐like reactivity within the tested dose and ultrasound window, as rising pH acts as a feedback switch to prevent hyperpolarization. We developed a boronate ester‐based delivery strategy featuring boronate ester/sialic‐acid‐assisted cellular association with mainly clathrin‐mediated endocytosis and partial tolerance to ATP depletion. This piezo‐Fenton‐like mediated mitochondrial modulation rescued impaired autophagic flux (from 8% to 35%) and preserved 89% of the average intervertebral disc height relative to the untreated blank control group in the in vivo rat model. This work provides a mechanically modulated metabolic reprogramming paradigm and highlights the promising application prospect of ultrasound‐responsive biomaterials in the treatment of degenerative diseases.