Saturday, November 23, 2024
11/23/2024
SUMMARY Ultrasound is among the world’s most widely used biomedical imaging technologies due to its low cost and ability to visualize deep tissues with high spatial and temporal resolution. However, ultrasound has had a relatively small role in molecular and cellular imaging due to a lack of contrast agents and reporter genes connected to specific aspects of cellular function such as gene expression and intracellular signaling. To address this limitation, we are developing acoustic biomolecules – proteins that can be imaged with ultrasound. These constructs are based on gas vesicles (GVs) – a unique class of air-filled protein nanostructures from buoyant photosynthetic microbes, which we introduced as imaging agents for ultrasound in 2014 (Nature Nano. 9:311) and as acoustic reporter genes for commensal microbes in 2018 (Nature 554:86). Since our last renewal, we took the next major step of demonstrating that GVs can function as reporter genes in mammalian cells (Science 365:1469, 2019 and Nature Biotech. 2023), learned how to turn GVs into dynamic biosensors of intracellular protease activity (Nature Chem. Biol. 16:988, 2020), developed methods to detect GV-expressing cells down to single-cell sensitivity (Nature Methods 18:945, 2021), demonstrated their utility as injectable contrast agents in a disease context (ACS Nano 14:12210, 2020), and made several other advances in understanding and engineering GVs and accompanying ultrasound methods and applications. Much work remains to be done to develop GVs as targeted nanoscale contrast agents and reporter genes with broad utility in biology and medicine. Our proposed next steps will enable specific applications of GVs in biomedical research and clinically relevant contexts. These next steps include developing GVs as both targeted nanoscale contrast agents and acoustic reporter genes, focusing on biomedically impactful applications in (1) labeling tumors for intraoperative ultrasound imaging and (2) visualizing the migration and proliferation of primary immune cells during immunotherapy. We will support the future clinical translation of these applications by establishing standardized protocols for high quality GV production, characterizing and optimizing their in vivo tolerability and immunogenicity and developing new nonlinear pulse sequences allowing ultrasound to nondestructively image lower doses of injected GVs and smaller numbers of GV-expressing cells. Successful completion of this work will result in unprecedented capabilities for ultrasonic molecular and cellular imaging and lay the foundation for developing clinical nanoscale and cell-based diagnostics and therapeutics.
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