Magnetic-field-driven targeting of exosomes modulates immune and metabolic changes in dystrophic muscle

Chiara Villa; Valeria Secchi; Mirco Macchi; Luana Tripodi; Elena Trombetta; Desiree Zambroni; Francesco Padelli; Michele Mauri; Monica Molinaro; Rebecca Oddone; Andrea Farini; Antonella De Palma; Laura Varela Pinzon; Federica Santarelli; Roberto Simonutti; Pier Luigi Mauri; Laura Porretti; Marcello Campione; Domenico Aquino; Angelo Monguzzi; Yvan Torrente

doi:10.1038/s41565-024-01725-y

Magnetic-field-driven targeting of exosomes modulates immune and metabolic changes in dystrophic muscle

Chiara Villa, Valeria Secchi, Mirco Macchi, Luana Tripodi, Elena Trombetta, Desiree Zambroni, Francesco Padelli, Michele Mauri, Monica Molinaro, Rebecca Oddone, Andrea Farini, Antonella De Palma, Laura Varela Pinzon, Federica Santarelli, Roberto Simonutti, Pier Luigi Mauri, Laura Porretti, Marcello Campione, Domenico Aquino, Angelo MonguzziYvan Torrente^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Exosomes are promising therapeutics for tissue repair and regeneration to induce and guide appropriate immune responses in dystrophic pathologies. However, manipulating exosomes to control their biodistribution and targeting them in vivo to achieve adequate therapeutic benefits still poses a major challenge. Here we overcome this limitation by developing an externally controlled delivery system for primed annexin A1 myo-exosomes (Exo^myo). Effective nanocarriers are realized by immobilizing the Exo^myo onto ferromagnetic nanotubes to achieve controlled delivery and localization of Exo^myo to skeletal muscles by systemic injection using an external magnetic field. Quantitative muscle-level analyses revealed that macrophages dominate the uptake of Exo^myo from these ferromagnetic nanotubes in vivo to synergistically promote beneficial muscle responses in a murine animal model of Duchenne muscular dystrophy. Our findings provide insights into the development of exosome-based therapies for muscle diseases and, in general, highlight the formulation of effective functional nanocarriers aimed at optimizing exosome biodistribution.

Original language	English
Pages (from-to)	1532-1543
Number of pages	12
Journal	Nature Nanotechnology
Volume	19
Issue number	10
DOIs	https://doi.org/10.1038/s41565-024-01725-y
Publication status	Published - Oct 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

This study was supported by the RF-2016-02362263 'Multimodal nanotracking for exosome-based therapy in DMD' (theory enhancing), 'Isolamento di nanoparticelle naturali da utilizzare come agenti anti-infiammatori/anti-fibrotici', 5 x 1000, Fondazione Patrimonio e dalla Direzione Scientifica Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (2022). The Torrente laboratory is also funded by 'Multiomics pRofiling of patient spEcific Models to predict druggable targets in severe neuromuscular rare diseases (REMODEL)', Unmet Medical Needs, Fondazione Regionale per la Ricerca Biomedica (FRRB) (2022), 'At the origin of congenital muscular dystrophy: shedding light on the Tdark proteins DPM2 and DPM3', Bando 'Cariplo Telethon Alliance GJC2021' (2022), 'Nanoparticles in Freidreich Ataxia' National Center for Gene Therapy and Drugs based on RNA Technology, Spoke #1: Genetic diseases, PNRR CN3 RNA, 2022, Associazione Centro Dino Ferrari. A.M. is funded by PNRR CN3 RNA, 2022, PNRR project ANTHEM: AdvaNced Technologies for Human-centrEd Medicine-PNC0000003 Spoke #2-NextGenerationEU. The funders of the study had no role in the study design, data analysis, data interpretation or writing of the report. We thank V. Berno for outstanding assistance in the acquisition and interpretation of the Amnis imaging flow cytometry data. We also thank S. Gatti for the use of the Bruker 2D U-OI system for bioluminescence studies. We thank A. Bianchi for his help in realizing the artificial circulatory system model.

Funders	Funder number
Regione Lombardia (Region of Lombardy)	RF-2016-02362263
Fondazione Patrimonio e dalla Direzione Scientifica Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Unmet Medical Needs, Fondazione Regionale per la Ricerca Biomedica (FRRB)	GJC2021, 2022, PNC0000003

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s41565-024-01725-yFinal published version, 7.4 MBLicence: CC BY

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Villa, C., Secchi, V., Macchi, M., Tripodi, L., Trombetta, E., Zambroni, D., Padelli, F., Mauri, M., Molinaro, M., Oddone, R., Farini, A., De Palma, A., Varela Pinzon, L., Santarelli, F., Simonutti, R., Mauri, P. L., Porretti, L., Campione, M., Aquino, D., ... Torrente, Y. (2024). Magnetic-field-driven targeting of exosomes modulates immune and metabolic changes in dystrophic muscle. Nature Nanotechnology, 19(10), 1532-1543. https://doi.org/10.1038/s41565-024-01725-y

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abstract = "Exosomes are promising therapeutics for tissue repair and regeneration to induce and guide appropriate immune responses in dystrophic pathologies. However, manipulating exosomes to control their biodistribution and targeting them in vivo to achieve adequate therapeutic benefits still poses a major challenge. Here we overcome this limitation by developing an externally controlled delivery system for primed annexin A1 myo-exosomes (Exomyo). Effective nanocarriers are realized by immobilizing the Exomyo onto ferromagnetic nanotubes to achieve controlled delivery and localization of Exomyo to skeletal muscles by systemic injection using an external magnetic field. Quantitative muscle-level analyses revealed that macrophages dominate the uptake of Exomyo from these ferromagnetic nanotubes in vivo to synergistically promote beneficial muscle responses in a murine animal model of Duchenne muscular dystrophy. Our findings provide insights into the development of exosome-based therapies for muscle diseases and, in general, highlight the formulation of effective functional nanocarriers aimed at optimizing exosome biodistribution.",

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Villa, C, Secchi, V, Macchi, M, Tripodi, L, Trombetta, E, Zambroni, D, Padelli, F, Mauri, M, Molinaro, M, Oddone, R, Farini, A, De Palma, A, Varela Pinzon, L, Santarelli, F, Simonutti, R, Mauri, PL, Porretti, L, Campione, M, Aquino, D, Monguzzi, A & Torrente, Y 2024, 'Magnetic-field-driven targeting of exosomes modulates immune and metabolic changes in dystrophic muscle', Nature Nanotechnology, vol. 19, no. 10, pp. 1532-1543. https://doi.org/10.1038/s41565-024-01725-y

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AU - Villa, Chiara

AU - Secchi, Valeria

AU - Macchi, Mirco

AU - Tripodi, Luana

AU - Trombetta, Elena

AU - Zambroni, Desiree

AU - Padelli, Francesco

AU - Mauri, Michele

AU - Molinaro, Monica

AU - Oddone, Rebecca

AU - Farini, Andrea

AU - De Palma, Antonella

AU - Varela Pinzon, Laura

AU - Santarelli, Federica

AU - Simonutti, Roberto

AU - Mauri, Pier Luigi

AU - Porretti, Laura

AU - Campione, Marcello

AU - Aquino, Domenico

AU - Monguzzi, Angelo

AU - Torrente, Yvan

PY - 2024/10

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N2 - Exosomes are promising therapeutics for tissue repair and regeneration to induce and guide appropriate immune responses in dystrophic pathologies. However, manipulating exosomes to control their biodistribution and targeting them in vivo to achieve adequate therapeutic benefits still poses a major challenge. Here we overcome this limitation by developing an externally controlled delivery system for primed annexin A1 myo-exosomes (Exomyo). Effective nanocarriers are realized by immobilizing the Exomyo onto ferromagnetic nanotubes to achieve controlled delivery and localization of Exomyo to skeletal muscles by systemic injection using an external magnetic field. Quantitative muscle-level analyses revealed that macrophages dominate the uptake of Exomyo from these ferromagnetic nanotubes in vivo to synergistically promote beneficial muscle responses in a murine animal model of Duchenne muscular dystrophy. Our findings provide insights into the development of exosome-based therapies for muscle diseases and, in general, highlight the formulation of effective functional nanocarriers aimed at optimizing exosome biodistribution.

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ER -

Magnetic-field-driven targeting of exosomes modulates immune and metabolic changes in dystrophic muscle

Abstract

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