Combining Sonodynamic Therapy with Nanocarriers: Enhancing Treatment Targeting and Efficacy

Sonodynamic therapy (SDT) is a non-invasive treatment modality that leverages the deep tissue penetration and spatiotemporal controllability of ultrasound to activate sonosensitizers and induce cytotoxic bioeffects, predominantly through reactive oxygen species (ROS)-mediated oxidative stress and cavitation-associated mechanical injury. Despite encouraging progress, early SDT development has been limited by poor aqueous solubility and nonspecific biodistribution of many sonosensitizers, inadequate intratumoral accumulation, and challenges in standardizing and monitoring ultrasound dosimetry. Nanocarrier technologies have substantially expanded the therapeutic design space of SDT by improving pharmacokinetics, reducing off-target exposure, preserving sensitizer activity (e.g., mitigating aggregation-related quenching), and enabling tumor- and organelle-directed delivery. This review summarizes the historical evolution of SDT and nanocarriers and synthesizes current mechanistic understanding, including cavitation-centered biophysics, multi-route ROS generation (sonochemistry, conditional sonoluminescence pathways, and mechano-electronic charge-redox processes), and downstream regulated cell death and immunogenic cell death. We further organize SDT-nanocarrier synergy into key modules: pharmacokinetic/spatial control, ultrasound-enhanced transport (sonoporation and barrier modulation), hypoxia relief and redox reprogramming to amplify ROS, engineered cavitation/energy transduction, and immune reprogramming enabling sono-immunotherapy. Finally, we discuss emerging application strategies-targeted delivery, tumor microenvironment modulation, and multimodal combination regimens-alongside translational progress and remaining barriers such as delivery heterogeneity, real-time exposure verification, long-term biosafety, manufacturability, and clinical trial design. Future advances are expected to prioritize simplified GMP-compatible platforms, delivery diagnostics for patient stratification, and closed-loop ultrasound control for consistent, safe, and precision SDT.