Ultrasound-Triggered Site-Specific Chemistry Redefines Precision Oncology

Abstract Ultrasound-triggered site-specific molecular chemistry has emerged as a transformative strategy for cancer therapy, yet precise spatiotemporal control of their activity remains a critical bottleneck. Endogenous stimulus-responsive strategies are hampered by tumor heterogeneity, while exogenous physical triggers provide superior controllability. This article proposes that ultrasound-triggered site-specific chemistry, termed “acoustic programming”, offers a transformative solution. By integrating focused ultrasound deep-tissue penetration with molecular-level chemical control, acoustically programmable bioconjugates achieve deep-tissue, on-demand therapeutic activation. We survey recent advances in sono-labile linkers, ultrasound-triggered charge reversal, and sono-chemically activated prodrugs, and critically evaluate emerging proof-of-concept and in vivo validated applications in ultrasound-caged PROTACs, immunomodulators, and antibody-drug conjugates. This paradigm shift from “ultrasound-responsive materials” to “ultrasound-responsive molecules” positions acoustic programming as a core platform technology for next-generation precision oncology.