Sono-piezoelectric cues regulate neuroinflammatory reflex-arc-mediated α7nAChR-P2RX7 axis to dampen osteoarthritis-correlated pain with osteoarthritis attenuation.

Background: Osteoarthritis (OA) characterized by progressive cartilage degeneration and chronic pain is hindered by the vicious inflammation-pain cycle. Nonsteroidal anti-inflammatory drugs (NSAIDs) can only alleviate clinical symptoms. Although electrical stimulation of the vagus nerve has achieved some results, the toxicity of the electrodes and the secondary damage caused by dismantling limited its clinical application. Methods: A "sono-piezoelectric-bioelectricity-neuroimmune" cascade modulation strategy based on ultrasound-driven piezoelectric ZnO nanoparticles was established to attenuate osteoarthritic neurogenic inflammation and pain with inhibited cartilage degradation. Results: The "sensory neuron-cholinergic anti-inflammatory pathway" reflex arc was activated by the dynamically and spatially-temporally programmed sono-piezoelectric field (0.7 V/36 μA peak) within deep joint tissues by targeting α7nAChR-P2RX7 neuroimmune axis. Consequently, our sono-piezoelectric neuroimmune modulation strategy significantly up-regulated α7nAChR expression, and synchronously inhibited pain mediator CX3CL1, opposed macrophage infiltration, inhibited P2RX7-mediated IL-1β/IL-6 inflammatory storm, restored IL-1β-injured chondrocyte activity and migration capacity, activated stromal genes (Col2a1) for matrix synthesis, and inhibited cartilage degradation-related MMP13 expression. All these actions re-established the balance of glycosaminoglycan (GAG)/deoxyribonucleic acid (DNA) metabolism to remodel joint immune homeostasis, and activated the cholinergic pathway to break the vicious cycle of "inflammation-pain", which restored mechanical pain threshold (Von Frey) and weight-bearing capacity to near-normal levels and reconstructed tidal structures in a rat OA model. Conclusions: Our pioneering "sono-piezoelectrical signal-neural reflex-immunomodulation" cascade strategy for regulating neuroinflammatory reflex-arc-mediated α7nAChR-P2RX7 axis provide deep insights into OA-represented neuroinflammatory diseases.