Ultrasound‐Responsive Extracellular Vesicle‐Encapsulated Piezoelectric Nanoparticles for Chronic Inflammatory Pain Suppression

Abstract

Chronic inflammatory pain is characterized by the long‐term coexistence of central sensitization and neuroinflammation. Electrical stimulation has been demonstrated to be an effective strategy for alleviating chronic inflammatory pain. However, implanted electrodes have limited lifespan and inevitably lead to tissue damage and potential neurological side effects. Here, a composite piezoelectric nanoparticle is constructed through the cooperative self‐assembly of phenylalanine dipeptides (FF) and metal–organic frameworks (MOFs), followed by the introduction of plant‐derived extracellular vesicles as a biointerfacial modification layer, thereby markedly enhancing its stability in brain tissue and transmembrane transport capability. Upon ultrasonic excitation, these nanoparticles efficiently localize to the cell nucleus and generate localized piezoelectric signals. In vivo, ultrasound‐activated UIONF@EVs significantly suppressed aberrant astrocyte activation and NF‐κB‐mediated transcriptional activity, accompanied by a marked reduction in the expression of key pro‐inflammatory cytokines, thereby producing pronounced analgesic effects. These findings provide a potential strategy for extending wireless piezoelectric neuromodulation toward intranuclear electrical regulation and offer a minimally invasive therapeutic approach for chronic inflammatory pain.