Current advances in ultrasound contrast agents are shifting the paradigm from the golden standard microbubbles to ultrasound-sensitive liquid nanoemulsions that are comprised of a fluorous phase-changing interior that vaporizes upon ultrasound exposure. Fluorous nanoemulsions are emergent nanomaterials that have enjoyed accelerating clinical and research interest due to their potential as multimodal contrast agents and spatiotemporally controlled delivery systems. Yet, despite recent progress, difficulties in loading bioactive cargo into the hydrophobic and lipophobic fluorous carrier interior, and efficiently releasing it to cells, remains a key barrier to their broad biomedical utility. Here, we report the discovery of a biofluorination strategy affording protein encapsulation into the fluorous carrier interior by using fluoroalkyl amphiphiles – a solubility barrier analogous to dissolving egg protein on a Teflon non-stick pan. The fluoroalkyl amphiphiles transiently complex with proteins to mediate efficient dispersion into ultrasound-sensitive perfluorocarbons via favored fluorine-fluorine interactions. Preparation of protein-loaded fluorous nanoemulsions, accessible through this unique biofluorination strategy, enables image-guided spatiotemporal delivery of proteins into cells using clinically relevant diagnostic ultrasound. The fluoroalkyl amphiphile dissociates from the protein cargo upon cytosolic delivery confirmed by biochemical and biophysical studies, and Doppler imaging monitors protein-loaded fluorous nanoemulsion acoustic activation in real-time. Through the biofluorination strategy, loading proteins into ultrasound-sensitive fluorous nanoemulsions has the potential to advance as a new theranostic system for image-guided cytosolic protein delivery with spatiotemporal precision.

Ultrasound-sensitive fluorous nanoemulsions enable image-guided cytosolic protein delivery

2019 Fall National Meeting

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