Microenvironment‐Responsive Piezoelectric Nanofibers Antagonize Chemotherapy‐Induced Peripheral Neuropathy

Abstract Chemotherapy‐induced peripheral neuropathy (CIPN), a severe neurological complication caused by chemotherapeutic agents, posed a significant challenge in pain management due to its complex pathogenesis involving oxidative stress, neuroinflammation, and metabolic dysregulation. Herein, the study develops novel microenvironment‐responsive piezoelectric nanofibers (PPK) with piezoelectric nanoparticles by electrospinning, which can be applied to alleviate CIPN with ultrasound. The thioether bond in PPK nanofibers underwent phase transformations in ROS environments, which endowed the nanofiber with ROS sensitivity. Furthermore, ultrasound induced piezoelectric PPK nanofibers with enhanced electrokinetic effect. Cellular experiments validate the robust ROS scavenging ability of the PPK nanofibers alongside high biocompatibility. Moreover, PPK nanofibers exhibit marked downregulation of inflammatory factors in nerve cells. Notably, after the implantation in CIPN rats, the PPK nanofibers are found to sustain accumulation at the dorsal root ganglion (DRG) area and significantly alleviate thermal hyperalgesia and mechanical allodynia. Moreover, the treatment using PPK nanofibers demonstrates attenuation of neuroinflammation and satellite glial cells activation in DRGs of CIPN rats. To investigate the underlying mechanism, transcriptomic profiling further unveils PPK‐mediated activation of glycolytic pathways and metabolic reprogramming, which potentially provide new clues for neural recovery. Collectively, this work establishes a promising therapeutic platform for mitigating CIPN and other neurological complications.