Enhancing Intratumoral Penetration in Solid Tumors Using Ultrasound-Responsive Gas-Generating PLGA Nanobubbles

The dense tumor microenvironment (TME) of solid tumors imposes formidable physical barriers that severely restrict deep intratumoral drug penetration. To overcome these limitations, we developed an ultrasound-responsive, nitric oxide (NO) gas-loaded poly (lactic-co-glycolic acid) (PLGA) nanobubble system. Upon targeted ultrasound irradiation, these nanobubbles trigger the localized release of the encapsulated NO gas alongside mechanical cavitation. This gas-driven biological remodeling profoundly dismantles interstitial transport barriers, facilitating the deep tissue penetration of the nanocarriers. Experimental results demonstrate that the combination of targeted gas release and cavitation achieves a remarkable 77.4% reduction in Type I collagen density, leading to highly enhanced and uniform accumulation of the therapeutic agents in both the deep cores of 3D multicellular tumor spheroids (MCTSs) and ex vivo tumor tissues. Ultimately, by leveraging ultrasound-responsive gas release to forcibly enhance intratumoral penetration, this nanobubble system offers a highly effective non-invasive paradigm for deep-seated solid tumor therapy.