Nanopiezoelectric 3D-Bioprinted Neural Organoid Models Epileptic Neuron–Microglia Circuit in Neurodegeneration

Epilepsy is increasingly linked to neurodegeneration, yet the cellular drivers of the neuron-microglia interplay remain unclear. Herein, we present "EpiNeuroid", a 3D-bioprinted human neural organoid that incorporates barium titanate piezoelectric nanoparticles to generate an on-demand, ultrasound-triggered electrostimulatory microenvironment that induces a hyperexcitable state, recapitulating key electrophysiological signatures indicative of a trend toward epileptiform discharges. EpiNeuroid recapitulates neuronal DAMPs release (HMGB1, TLR4, NF-κB), microglial activation (Iba1, TNF-α, IL-1β, IL-6, iNOS), heightened neuronal Ca²⁺ influx, and progressive viability loss, with microglia amplifying injury and hyperexcitability to establish a self-perpetuating epilepsy-neurodegeneration loop. To enable therapeutic screening, we engineered self-assembled ginsenoside protopanaxadiol nanorods (PPD-NRs), which outperformed free protopanaxadiol by suppressing BDNF/ERK/CREB/mTOR hyperactivation, reducing cytokines and HMGB1, restoring Ca²⁺ homeostasis, and preserving neurosphere integrity. Collectively, EpiNeuroid provides a human-relevant, tunable platform for the mechanistic dissection and discovery of nanotherapeutic interventions in epilepsy-associated neurodegeneration.