Efficient exosome delivery in refractory tissues assisted by ultrasound-targeted microbubble destruction

Abstract

Recently, exosomes have been emerged as promising drug delivery carriers, while certain tissues are intrinsically resistant to exosomes. Therapeutically improving the drug delivery efficiency in these tissues/organs would certainly broaden the potential application of exosomes in future. Ultrasound-targeted microbubble destruction (UTMD) is a promising technique for non-invasive, targeted drug delivery. In this study, we explore the possibility that UTMD assists exosome delivery in these intrinsically resistant tissues. Mice were subjected to tail vein injection of DiR-labeled exosomes together with/without UTMD of SonoVueTM, followed by in vivo and ex vivo tracking of the exosomes. As expected, heart, adipose tissue, and skeletal muscle were found reluctant to exosomes from different origins. Targeted destruction of the ultrasound microbubbles (SonoVueTM) in the heart and adipose tissue region significantly increased the exosome infiltration and endocytosis there, as revealed by fluorescence imaging and confocal laser scanning microscope (CLSM). UTMD treatment 1 h prior to exosome injection failed to facilitate the exosome endocytosis in the targeted region, indicating that the transient promoting effects of UTMD. Moreover, increases of UTMD (numerous pulses) did not linearly enhance the exosome delivery. Together, our study here has established a novel strategy for targeted delivery of exosomes in the reluctant tissues, by combining the advantages of ultrasound microbubbles and exosomes in drug delivery.

Brown adipose tissue-derived exosomes mitigate the metabolic syndrome in high fat diet mice

“…In regard with the specific working mechanism of exosomes, there is still a lot of work to do. Although we have demonstrated that exosomes predominately accumulate in liver after intravenous injection which is consistent with other researches, there are still a small population of exosomes that will circulate into heart and WAT 50 , 51 . It is thus no doubt that some BAT-Exos could affect and regulate WAT and heart directly.…”

Hydrogel Encapsulation of Mesenchymal Stem Cells and Their Derived Exosomes for Tissue Engineering

“…Aside from using exosome-embedded hydrogels to achieve a topical and sustained drug release effect, when exosomes are not encapsulated in hydrogels, they are delivered intravenously or topically [ 80 ]. Sun and co-authors [ 80 ] have designed a delivery method that can topically release exosome at the target sites.…”

“…Aside from using exosome-embedded hydrogels to achieve a topical and sustained drug release effect, when exosomes are not encapsulated in hydrogels, they are delivered intravenously or topically [ 80 ]. Sun and co-authors [ 80 ] have designed a delivery method that can topically release exosome at the target sites. They also intravenously injected exosomes together with a SonoVue TM microbubble (Bracco Imaging) into mice, and then targeted the destruction of these microbubbles by ultrasound [ 80 ].…”

Mastering the Tools: Natural versus Artificial Vesicles in Nanomedicine

“…However, this approach did not have the desired effects and it has only been used for restricted applications. [187] In their paper, the authors demonstrated the possibility of loading EVs into mice refractory tissues by injecting SonoVue (sulfur hexafluoride) microbubbles together with the EVs and inducing UTMD. Microbubble destruction and the cavitation effect increased the infiltration of EVs in heart, adipose tissue, and skeletal muscles, as well as in liver and the reticuloendothelial system, [187] opening another promising way to increase the selectivity of EV targeting.…”

“…Indeed, given their higher flexibility in production and easier functionalization, polymersomes can be envisaged as an advantageous and cheaper alternative to liposomes. Extracellular vesicles + Difficult massive production and purification; biomolecules as only building blocks; limited tunability of the physicochemical properties [ 87,240] +++ Generally safe; extraction from biological sources with high biocompatibility [80,83] ++ Excellent loading of biomolecules; challenging loading of synthetic molecules; good delivery efficiency;rapid clearance [ 186,187] Liposomes ++ Easy production and purification; pre-and postsynthetic functionalization; tunable physicochemical properties [ 124,161] +++ Generally safe, unless modified with charged phospholipids; similar composition to EVs, but without cell-mediated modifications [103,213] ++ Good natural and synthetic molecules loading; preassembly and postassembly loading; good delivery efficiency; tunable clearance properties [ 198,199] Polymersomes +++ Customizable massive production; pre-and postsynthetic functionalization; tunable physicochemical properties [ 136,155] + Possible accumulations in the body; possibility to introduce biodegradable polymers [229,230] + Preassembly and postassembly loading; cell uptake dependent on the vesicle and cell membrane characteristic; tunable clearance properties [ 222,224]…”