<p>Noninvasive energy-based therapies such as photothermal, photodynamic, chemodynamic, and sonodynamic treatments can lower systemic toxicity, but their efficacy is limited by shallow light penetration and by hypoxic, antioxidant-rich microenvironments. Sonothermal therapy (STT) uses deeply penetrating ultrasound to activate engineered nanomaterials that convert acoustic energy into localized heat. This enables targeted hyperthermia and ultrasound-driven mechanical effects that improve drug delivery, ablate deep lesions, and help control drug-resistant infections. This review summarizes four coupling routes between ultrasound and nanomaterials: thermoelastic, thermoviscous and plasmonic heating; nonradiative recombination and acousto-electric coupling; thermal vibrations in carbon and conjugated systems; and cavitation heating. It then sets out design principles for STT nanomaterials with guidance for the periods before, during, and after treatment. These principles are linked to applications in tumor ablation, wound infection and healing, and implant-associated infection and regeneration. Hybrid platforms that combine STT with reactive oxygen species generation through sonodynamic or sonocatalytic processes are also discussed. Key barriers to translation are outlined, including the lack of quantitative and standardized metrics for conversion efficiency, the need for scalable and reproducible manufacturing aligned with Good Manufacturing Practice, limited <i>in vivo</i> biodistribution and biosafety data, and weak links from preclinical models to clinical endpoints. The review proposes an integrated framework that connects mechanism, material design, and therapeutic outcome to guide the development of next-generation STT nanoplatforms for treatment-resistant disease.</p>