Piezo1-Targeted Magnetoacoustic Nanobubbles Rescue Alzheimer's Pathology by Electromechanical Neuromodulation and Amyloid-β Clearance.

Amyloid-β (Aβ) is considered a core pathological feature of Alzheimer's disease (AD), and its clearance efficiency is highly dependent on the function of the Piezo1 channel in microglia. However, the activity of Piezo1 is impaired under the pathological conditions of AD, and existing pharmacological strategies struggle to achieve precise targeted intervention in deep brain regions. To address these concerns, our research proposes a synergistic therapeutic paradigm leveraging transcranial magneto-acoustic stimulation (TMAS) to actuate microglial-Piezo1-targeted magnetic nanobubbles (PT-MNBs) for AD treatment. TMAS noninvasively focuses physical energy into deep brain lesion areas through a magnetoacoustic coupling field and drives PT-MNBs to generate responsive mechanical and electrical stimulation signals. PT-MNBs achieve microglia-specific anchoring through surface-modified phosphatidylserine, while conjugated anti-Piezo1 antibodies precisely deliver mechano-electrical stimulation signals to antibody-functionalized Piezo1 ion channels in microglial populations. This synchronously activates the mechanical- and voltage- sensitive domains of Piezo1 to recruit microglia to areas of inflammation and increase Aβ clearance, ameliorating synaptic plasticity impairment and ultimately reversing the pathological progression of AD. This dual-action mechanism achieves spatially precise manipulation of cellular mechanical and electrical activity in deep brain regions of AD mice and enhances Piezo1 function through precise energy delivery, enhancing their ability to clear Aβ plaques, opening an avenue for a noninvasive, deep-targeted physical stimulation-mediated nanoparticle synergistic therapy for AD.