Tumors often exhibit extracellular matrix, which becomes stiffer due to excessive accumulation and cross-linking of proteins (especially collagen). This increased rigidity acts as a physical barrier, hindering the infiltration of immune cells and the effective delivery of various immunotherapy drugs (such as lipid nanoparticle RNA therapy). In this study, we explored the ability of ultrasound-activated nanobubbles (US-NBs) to enhance tumor permeability and immunogenicity. Our results showed that US-NBs achieved physical remodeling by reducing the hardness of tumor tissues by 60% within 5 days after a single treatment. The collagen in US-NB treatment was randomly arranged, and the deposition rate was 5.47 times lower than that of untreated tumors. This is conducive to the effective delivery and widespread distribution of lipid nanoparticles (LNPs) within the tumor. Importantly, with the assistance of US-NBs, LNPs demonstrated superior gene transfection efficiency among general immune cells and achieved efficient gene modification of T cells in vivo. This combined method involves both innate and adaptive immunity, enhances tumor immunogenicity, and increases the infiltration rate of cytotoxic cells by 4 times, which is 4 times higher than that of simple LNPs. These results indicate that using US-NBs for gentle mechanical stimulation of tumors provides a promising strategy for enhancing the delivery and efficacy of existing immunotherapies. This study was published in ACS Nano under the title "Enhanced Delivery of Lipid Nanoparticle-Based Immunotherapy by Modulating Tumor Tissue Stiffness Using Ultrasound-Activated Nanobubbles".
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DOI: 10.1021/acsnano.5c21787