Ultrasound-activated piezoelectric patch enhances mitophagy and synergistic anti-inflammation to promote neurological repair after TBI

Abstract

Mitochondrial dysfunction following traumatic brain injury (TBI) is a central pathological driver of secondary neuronal damage and neuroinflammation. Mitophagy, a key mitochondrial quality control mechanism, is essential for maintaining neuronal homeostasis and promoting injury repair. However, achieving spatiotemporally precise regulation of mitophagy while simultaneously modulating the neuroimmune microenvironment remains a major challenge. Here, we design an implantable piezoelectric patch that, upon activation by low-intensity pulsed ultrasound (LIPUS), generates controllable local electrical signals at the injury site and directly acts on damaged neurons. The patch predominantly upregulates Piezo1-sensitive mechanotransduction and induces a transient elevation of mitochondrial Ca2+, thereby contributing to enhanced PINK1/Parkin-associated mitophagy flux. This facilitates the clearance of damaged mitochondria, restores mitochondrial membrane potential, and alleviates oxidative neuronal injury (apoptosis rate reduced from 30.42% to 11.78%). Concurrently, the treatment reduces mitochondrial DNA (mtDNA) leakage and the release of pro-inflammatory factors, driving microglial polarization toward the protective M2 phenotype and remodeling the neuroimmune microenvironment. In a mouse model of TBI, this synergistic strategy significantly suppresses neuronal apoptosis, reduces brain tissue loss, increases neuronal survival in the peri-lesional area (3.5-fold increase in NeuN mean fluorescence intensity compared to the TBI group), and decreases glial scar formation, ultimately leading to substantial improvements in motor and cognitive functions. This study presents a piezoelectric-based strategy for TBI therapy that couples mitophagy regulation with neuroimmune remodeling, offering new insights into materials design and potential translational avenues for precise repair of central nervous system injuries.