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

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 Fe3 +/Fe2 + 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.