An Arginine-Engineered Piezoelectric Conjugated Polymer for Sonodynamic Therapy via Enhanced Cellular Uptake and...

Sonodynamic therapy (SDT) is often compromised by the hypoxic tumor microenvironment and the limited lethality of primary reactive oxygen species (ROS). Herein, we report a piezoelectric conjugated polymer sonosensitizer, PFT-PArg, engineered with a donor-acceptor (D-A) backbone and l-arginine (l-Arg) side chains to overcome these limitations. The asymmetric D-A skeleton endows PFT-PArg with intrinsic piezoelectricity, driving efficient ultrasound-induced electron transfer to generate superoxide anions (O₂^•-). Concurrently, the l-Arg moieties facilitate active tumor accumulation and metabolize into nitric oxide (NO), which not only alleviates hypoxia but reacts in situ with piezoelectric-generated O₂^•- to yield highly cytotoxic peroxynitrite (ONOO^•-). This ″piezo-chemical″ cascade amplifies oxidative stress, causing irreversible DNA damage and mitochondrial dysfunction. Consequently, PFT-PArg achieves potent tumor eradication in 4T1 tumor-bearing mice, establishing a high-performance SDT paradigm through the integrated synergy of electron transfer and gas-mediated sensitization.