Hydrogen-Bonding-Stabilized Organic Piezoelectric Nanofibers for Immunogenic Sonopiezodynamic Therapy of Metastatic Tumors.

Piezoelectric biomaterials enable mechano-electrical coupling in biological systems, facilitating real-time sensing, actuation, and in vivo energy harvesting. However, their application is constrained by the scarcity of stable organic piezoelectric systems. Here, we develop a one-step electrospinning strategy for self-assembling organic heterostructured piezoelectric nanofibers to combat tumor metastasis. In this system, directional hydrogen bonding between the ─NH2 groups of diphenylalanine (FF) and the C═O groups of poly(L-lactic acid) (PLLA), alongside van der Waals interactions, critically promotes oriented PLLA chain crystallization and stabilizes the piezoelectric β-phase. The resulting PLLA@FF composite exhibits enhanced piezoelectric performance and excellent stability. Under ultrasound irradiation, injectable PLLA@FF generates a potent sonopiezoelectric effect, triggering a reactive oxygen species storm that induces mitochondrial dysfunction, robust apoptosis, and the release of damage-associated molecular patterns, thereby initiating an immunogenic cell death cascade. In vivo studies demonstrate that PLLA@FF-mediated sonopiezoelectric therapy not only suppresses primary and distant tumor growth but also inhibits lung metastasis by remodeling the immunosuppressive tumor microenvironment. RNA sequencing further corroborates these findings, revealing activation of oxidative stress, apoptosis, and immune-related pathways. Collectively, this work overcomes the stability limitations of piezoelectric polymers and establishes a versatile, biodegradable fibrous platform for advanced piezocatalytic immunotherapy.