Ultrasound-responsive microbubble platforms in lung cancer: mechanisms, molecular targeting, and therapeutic applications

Lung cancer remains a major cause of cancer-related mortality, while the heterogeneous tumor microenvironment, abnormal vasculature, elevated interstitial fluid pressure, hypoxia, and dense extracellular matrix substantially limit the efficacy of conventional systemic therapies. Ultrasound-responsive microbubbles (MBs) have emerged as versatile theranostic platforms capable of overcoming several of these delivery barriers through externally controlled acoustic cavitation. This review comprehensively discusses the evolution, physicochemical characteristics, composition, and functional mechanisms of MB-based systems for lung cancer diagnosis and therapy. Particular emphasis is placed on stable and inertial cavitation, sonoporation, microstreaming, vascular permeabilization, and enhanced transport of therapeutic agents into tumor tissue. The diagnostic potential of targeted MBs for contrast-enhanced ultrasound, molecular imaging, perfusion assessment, and super-resolution visualization of tumor vasculature is highlighted. Therapeutic applications encompassing chemotherapeutics, nucleic acids, microRNAs, oxygen delivery, immunotherapy, and combination strategies with radiotherapy are critically examined. The review also discusses molecularly targeted MBs, nanoparticle–MB hybrids, and ultrasound-triggered modulation of the tumor immune microenvironment. Despite promising preclinical outcomes, challenges involving pulmonary acoustic attenuation, short circulation time, biodistribution, treatment parameter standardization, manufacturing, safety, and regulatory requirements remain. Emerging theranostic, hybrid, and artificial intelligence-assisted platforms may facilitate personalized and clinically translatable microbubble-based precision therapy for lung cancer.