2. Academic Validation
  3. Piezoelectric nanoparticle-driven rhythmic ultrasound neuromodulation for treatment of early-stage Alzheimer's disease

Piezoelectric nanoparticle-driven rhythmic ultrasound neuromodulation for treatment of early-stage Alzheimer's disease

  • Biomaterials. 2026 May:328:123905. doi: 10.1016/j.biomaterials.2025.123905.
Xiaoxia Li 1,  Sicheng Yan 2,  Mingding Li 3,  Renyuan Liu 4,  Qiangbing Lu 2,  Minghui Lu 5,  Feng Bai 6,  Qun-Dong Shen 7
Affiliations

Affiliations

  • 1 Department of Neurology, Affiliated Nanjing Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210009, China; Department of Polymer Science and Engineering, Key Laboratory of High-Performance Polymer Materials and Technology of MOE, State Key Laboratory of Analytical Chemistry for Life Science, Engineering Research Center of Photoresist Materials of MOE, School of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210023, China.
  • 2 National Laboratory of Solid-State Microstructures, Department of Materials Science and Engineering, Nanjing University, Nanjing, 210093, China.
  • 3 Department of Polymer Science and Engineering, Key Laboratory of High-Performance Polymer Materials and Technology of MOE, State Key Laboratory of Analytical Chemistry for Life Science, Engineering Research Center of Photoresist Materials of MOE, School of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210023, China; Key Laboratory of Materials & Surface Technology (MOE), School of Materials Science and Engineering, Xihua University, Chengdu, 610039, China.
  • 4 Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210009, China.
  • 5 National Laboratory of Solid-State Microstructures, Department of Materials Science and Engineering, Nanjing University, Nanjing, 210093, China; Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing, 210093, China. Electronic address: [email protected].
  • 6 Department of Neurology, Affiliated Nanjing Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210009, China. Electronic address: [email protected].
  • 7 Department of Neurology, Affiliated Nanjing Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210009, China; Department of Polymer Science and Engineering, Key Laboratory of High-Performance Polymer Materials and Technology of MOE, State Key Laboratory of Analytical Chemistry for Life Science, Engineering Research Center of Photoresist Materials of MOE, School of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210023, China. Electronic address: [email protected].
PMID: 41389410 DOI: 10.1016/j.biomaterials.2025.123905
Abstract

Synaptic dysfunction and loss are central drivers of cognitive decline in Alzheimer's disease (AD), yet current therapeutic approaches targeting Amyloid-β or tau pathology have largely failed to rescue synaptic function. Neural oscillations and synaptic plasticity are tightly coupled and underpin functional brain networks, suggesting that modulating oscillatory dynamics may offer new therapeutic avenues. Here, we developed a strategy for precise, non-genetic neuromodulation using focused ultrasound and piezoelectric Ba0.85CA0.15Zr0.1Ti0.9O3 (BCZT) nanoparticles to generate targeted, gamma-frequency electromagnetic fields in the hippocampal CA3 subregion of early-stage AD mouse models. This rhythmic stimulation effectively restored impaired gamma oscillations, enhanced synaptic plasticity, and remodeled memory-related network connectivity, as validated by local field potential recordings, patch-clamp electrophysiology, and functional MRI. Mechanistically, we demonstrate that NF-κB transcription factor activation during rhythmic stimulation regulates AMPAR trafficking by balancing synaptic internalization and delivery, with concurrent upregulation of P300-mediated histone acetylation. Our findings establish a novel paradigm for spatially precise, periodic neuromodulation that restores hippocampal information processing and network function in early AD, highlighting the therapeutic potential of piezoelectric nanomaterials for neural circuit repair in AD and Other neurodegenerative diseases characterized by impaired neural rhythms.

Keywords

Alzheimer's disease; Low-intensity focused ultrasound; Neural oscillation; Piezoelectric nanoparticles; Wireless rhythmic neuromodulation.

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