Year: 2026
Type: article
Abstract: Therapeutic nucleic acid delivery has many potential applications, but it remains challenging to target extrahepatic tissues in a flexible and image-guided manner. To address this issue, we report a bioorthogonal pre-targeting strategy that uses focused ultrasound (FUS) to promote the delivery of mRNA-loaded lipid nanoparticles (mRNA-LNP). We synthesized amphiphilic click reactive anchors (ACRAs) consisting of a phospholipid PEG-conjugate functionalized with trans-cyclooctene (TCO) or its companion reactive partner methyltetrazine (mTz), producing ACRA-TCO and ACRA-mTz. ACRA derivatives were screened for cellular activity, yielding functionalized DOPE-PEG (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol)) derivatives outperforming those containing saturated lipid or branched PEG. Nanobubbles encapsulating ultrasound-responsive gas delivered ACRA-TCO to targeted cells and tissues using FUS. This pre-targeting promoted the subsequent delivery of mRNA-LNP functionalized with companion ACRA-mTz. Ultrasound pre-targeting enhanced the accumulation of mTz-functionalized nanoparticles in cell cultures and mice by 75% and up to 3.6-fold, respectively, and increased gene expression using mRNA-LNP in vivo. Microbubbles loaded with ACRA roughly doubled mRNA delivery to the heart, while ultrasound alone did not. Taken together, this report presents a modular, ultrasound-enabled strategy for enhancing nucleic acid delivery in targeted tissues.
Authors: Emilio Di Ianni, Jueun Jeon, Sedra Mohammadi, Huiyu Hu, Jeremy M. Quintana, Chanseo Lee, Edwina Abou Haidar, Marie Goemans, Ayrton Zargani‐Piccardi, Mohammed Mahamdeh, Iván Coto Hernández, Victoria E. Rodriguez, Yirong Zhou, Aaron Aguirre, Shiaulou Yuan, Thomas S.C. Ng, Koen Breyne, Hakho Lee, Xandra O. Breakefield, Miles A. Miller
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, American Heart Association, Pfizer, Massachusetts General Hospital, Ionis Pharmaceuticals, National Institutes of Health, Genentech, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Biomedical Imaging and Bioengineering
Awards: CAN EVS EXPAND THE THERAPEUTIC EFFECT OF GENE REPLACEMENT FOR TSC1 IN BRAIN, G1720163979, FIRING UP THE TUMOR MICRO-ENVIRONMENT IN METASTATIC PROSTATE CANCER WITH SYNERGISTIC PSMA-TARGETING RADIOLIGANDS AND STING AGONIST NANO-THERAPIES, Optimized and accessible immuno-PET using lipid nanoparticle-mediated in vivo bioreactor, Dissection of in situ myeloid signaling using image-guided synthetic control, Primary Cilia as Mechanical Load Sensors in Cardiomyocytes, Deep Learning Methods for Improving Gallium 68-Based PET Imaging, Interrogation of ciliary mechano-chemosensing in cardiac left-right patterning using holographic optical tweezers, Decoding the role of intra-ciliary calcium signaling in cardiac situs development, Unraveling the function of cilia as shear flow sensors during heart development via remote-controlled micro-robotics, G4119534169, DEVELOPMENT OF ANTI-DYT1 DYSTONIA GENE EDITING THERAPIES, G5850682332, G6078352458, The power of extracellular vesicles in glioblastoma, G8013038050, G9000097736, Boosting IL-12-induced anti-glioblastoma activity via immunotherapeutic extracellular vesicles., Molecular profiling of global tissue dynamics at sub cellular resolution, Optogenetic regulation of intra-ciliary calcium signaling in cardiac situs development, Imaging radiation-enhanced drug delivery for safer and more effective chemoradiotherapy, Integration of circulating tumor cell and nuclear imaging biomarkers to assess LuPSMA response and resistance in advanced prostate cancer patients, Expanding the therapeutic window of chemoradiation through radiation-responsive nanoparticle drug depots, The impact of upper gastrointestinal dysmotility on aspiration-associated aerodigestive disorders in children, Super-resolved multiphoton microscopy with dual output ultrafast laser
OpenAlex ID: W7125419690