Ultrasound-mediated targeted micro/nanobubbles: breaking new boundaries in precision tumor therapy

Malignant tumors pose a public health challenge due to escalating incidence and mortality. Traditional treatments suffer from poor target specificity between healthy and tumor tissues, resulting in severe side effects. Immunotherapy is a pivotal advancement, but it faces poor tumor penetration, low targeting efficiency, inadequate drug delivery, immune evasion, and drug resistance. To overcome these challenges, ultrasound-mediated targeted micro/nanobubbles (UMT-MNBs) emerge, which is a noninvasive, highly targeted, and nonviral vector novel therapeutic method for malignant tumors. This approach overcomes drug resistance and facilitates the targeted release of therapeutic molecules. Concurrently, MNBs activate the immune system, enhance immune cell filtration, suppress tumor angiogenesis, and induce immunogenic cell death (ICD). UMT-MNBs demonstrate synergistic potential with conventional therapies, showcasing substantial clinical promise. This review presents recent advances in UMT-MNBs for drug/gene delivery, hypoxia modulation, resistance mitigation, immune activation/regulation, and penetration of blood-brain barrier. It also introduces UMT-MNBs in combinatorial regimens, including chemo, radio, photothermal, photodynamic, and sonodynamic therapies, to reduce dosage, improve efficacy, and minimize toxicity, thereby advancing precision medicine in oncology. Finally, future research on UMT-MNBs is discussed. It is necessary to focus on optimizing ultrasound parameters, emphasizing surface functionalization of MNBs, elucidating the mechanisms of immune activation and regulation, and exploring multimodal combined treatment strategies. Our findings provide new insights into the visualization and real-time regulation capabilities of UMT-MNBs, driving the application of immunotherapy and combination therapies, opening new directions for targeted therapy, and facilitating breakthrough progress in cancer therapy.