Enhanced Delivery of Lipid Nanoparticle-Based Immunotherapy by Modulating the Tumor Tissue Stiffness Using Ultrasound-Activated Nanobubbles
1
Issued Date
2026-02-10
Resource Type
eISSN
1936086X
Scopus ID
2-s2.0-105029806270
Pubmed ID
41605132
Journal Title
ACS Nano
Volume
20
Issue
5
Start Page
4592
End Page
4606
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Nano Vol.20 No.5 (2026) , 4592-4606
Suggested Citation
Bhalotia A., Hutchinson D.W., Kosmides T., Nittayacharn P., Mehta M., Iyer A., Cheplyansky A., Takizawa K.H., Nidhiry A., Dever A.M., Cousens K.A., Hwang I.M., Ramamurthy G., Exner A.A., Karathanasis E. Enhanced Delivery of Lipid Nanoparticle-Based Immunotherapy by Modulating the Tumor Tissue Stiffness Using Ultrasound-Activated Nanobubbles. ACS Nano Vol.20 No.5 (2026) , 4592-4606. 4606. doi:10.1021/acsnano.5c21787 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/115176
Title
Enhanced Delivery of Lipid Nanoparticle-Based Immunotherapy by Modulating the Tumor Tissue Stiffness Using Ultrasound-Activated Nanobubbles
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Abstract
Tumors often exhibit an extracellular matrix with elevated stiffness due to excessive accumulation and cross-linking of proteins, particularly collagen. This elevated stiffness acts as a physical barrier, impeding the infiltration of immune cells and the effective delivery of various immunotherapeutic agents, such as lipid nanoparticle-based RNA therapeutics. Here, we investigate the ability of ultrasound-activated nanobubbles (US-NBs) to increase the permeability and immunogenicity of tumors. Our results show that US-NBs physically remodel the tumor tissue by decreasing its stiffness by 60% 5 days after a single treatment. US-NB-treated tumors display randomly oriented collagen with a 5.47-fold lower deposition compared to untreated tumors. This leads to the effective delivery and widespread distribution of lipid nanoparticles (LNPs) in the tumor. Importantly, when assisted by US-NB, LNPs exhibit superior gene-transfection efficiency across pan-immune cells and achieve efficient genetic modification of T cells directly in vivo. This combined approach engages both innate and adaptive immunity, enhancing tumor immunogenicity and boosting cytotoxic cell infiltration by 4-fold compared to LNPs alone. These results indicate that gentle mechanical stimulation of the tumor using US-NB offers a promising strategy to augment the delivery and efficacy of existing immunotherapies.