Ultrasound‐Responsive Piezo‐Fenton‐Like Microspheres for Modulating Mitochondrial Membrane Potential to Alleviate Intervertebral Disc Degeneration

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.