Multifunctional Ultrasound Microbubbles

Microbubbles (MBs) have served as ultrasound (US) contrast agents for over 30 years in cardiac imaging and liver tumor characterization. Moreover, in recent years, molecularly targeted MBs are currently under clinical evaluation for oncological and inflammatory diseases. Beyond diagnostics, MBs are gaining attention as therapeutic tools, leveraging their strong acoustic properties for US-mediated drug delivery, sonopermeation of biological barriers (i.e., the blood-brain barrier), and targeted thrombolysis. Loading MB shells with magnetic or optical functionalities allows therapy monitoring using magnetic resonance or photoacoustic imaging, aligning with recent multimodal advances in (pre)clinical device developments. Therefore, this review summarizes and critically assesses advances in the use of multifunctional MBs for biomedical applications. A comprehensive overview of existing MB formulations is provided, analyzing the primary types of functional agents incorporated, including small molecules, nanomaterials, and targeting ligands, as well as the conjugation and functionalization strategies involved in constructing next-generation MBs. Current trends in multifunctional MBs for imaging and therapy are critically evaluated, along with the challenges in their clinical translation. Overall, this review highlights the potential of multifunctional MBs to address unmet biomedical needs that plain additives cannot fulfill, and it showcases promising future directions for the diagnostic and therapeutic use of next-generation MB formulations.