Ultrasonic-driven force-electric nanodomains orchestrate lysosome-to-mitochondria functional cascade to accelerate...

Piezoelectric materials offer a promising bioinspired direction for bone regeneration by mimicking the native electromechanical environment of bone. However, existing studies mainly focus on extracellular piezoelectric cues perceived by cell membrane, while whether force-electric signals can be precisely regulated at subcellular functional units governing osteogenesis remains insufficiently understood. Here, we report an ultrasound-activated force-electric regulation strategy enabled by ultrafine LiNbO₃ nanoparticles (∼15 nm). Owing to their ultrafine size, these nanoparticles are efficiently internalized by stem cells and form intracellular force-electric nanodomains that generate localized electrical signals upon ultrasound stimulation, thereby avoiding nonspecific extracellular inflammatory activation and leading to markedly enhanced osteogenic activity. Mechanistically, these nanodomains perturb lysosomal membranes, enhance mitochondrial activity and establish a lysosome-to-mitochondria functional cascade. Transcriptomic analysis further identifies the PI3K-AKT-Ibsp axis as a key pathway mediating the osteoinductive effect. In a rabbit calvarial defect model, this force-electric regulation significantly accelerates bone regeneration. This work demonstrates that ultrasonic-driven ultrafine piezoelectric nanodomains enable spatially precise force-electric regulation by acting closer to subcellular functional units, establishing a materials-based strategy for bone tissue regeneration.