Engineering Nanosensitizer into Hierarchical Modulators for Sonodynamic Antibacterial Therapy

Abstract

The global escalation of antimicrobial resistance demands new therapeutic solutions to overcome the limitations of conventional antibiotics. Sonodynamic therapy (SDT), a non-pharmacological approach using ultrasound to activate sonosensitizers for localized reactive oxygen species (ROS) generation, offers significant potential. However, its clinical translation is restricted by the low ROS yields and the inadequacy of monomodal therapy against complex infections. To address these challenges, nanotechnology facilitates the rational engineering of advanced nano-sonosensitizers. Moving beyond conventional reviews that focus on cataloguing material compositions or elucidating isolated strategies to enhance SDT efficacy such as optimizing interfacial charge separation/transfer or boosting ROS yield, this review provides a systematic, function-oriented hierarchical design framework intended to guide the next generation of SDT nano-platforms. This framework is elucidated through a hierarchical engineering paradigm, organized across three synergistic levels: (1) Engineering of material architectures via heterojunction design to maximize ROS generation; (2) Construction of microenvironment-responsive antibacterial executors capable to overcome biofilm barriers; and (3) Orchestration of programmable therapeutic actuators that function as augmentable core, cooperative partner and programmable initiator within multimodal therapeutic cascades. Finally, we outline the translational challenges and future perspectives for developing next-generation SDT nanoplatforms to complex bacterial infections.