ULTRASOUND-TRIGGERED STIMULI-RESPONSIVE DRUG DELIVERY SYSTEMS: MECHANISMS, CARRIER DESIGN, CONTROLLED RELEASE, THERAPEUTIC APPLICATIONS AND TRANSLATIONAL CHALLENGES

Drug delivery systems activated by ultrasound are a novel type of drug delivery system that employs acoustical energy to control the release of medications and to alter tissue permeability, carrier disruption or bind therapy. Ultrasound allows to reach the target areas in a non-invasive manner, providing spatial and temporal control thanks to the possibility to modify frequency, pressure (amplitude), intensity, pulse length, duty cycle and shape of ultrasound beam, as well as to use ultrasound excitable chemicals when necessary. There are several mechanisms used in drug delivery activated with ultrasound; these are stable and inertial cavitation, sonoporation, ultrasound standing wave force, microstreaming, local heating and production of reactive oxygen species by the action of ultrasound waves. These basic mechanisms can be used in combination with microbubbles, nanobubbles, liposomes, polymer nanoparticles, nanodroplets, hydrogels, inorganic substances and composite carriers in order to provide slow-release, delayed burst, continuous, pulse or continuous-on-demand drug release characteristics. In the given article we present the cooperation of actions- the mechanism of drug interactions, combining acoustical parameters and characteristics of carrier item such as its physical and chemical properties, level of activation of these carriers and time of drug release. Therapeutic applications in cancer, neurological disorders, transdermal delivery, tissue regeneration, infection, and immunomodulation are discussed, together with imaging-guided and theranostic approaches. Key translational barriers include acoustic dosimetry, cavitation control, patient-to-patient variability, carrier stability, manufacturing scale-up, device-drug combination regulation, and limited clinical validation. Recent developments in adaptive ultrasound, smart biomaterials, multi-stimuli systems, and feedback-controlled treatment may support more reproducible and personalized ultrasound-mediated drug delivery.