Nanoparticles fate and transport in extracellular vesicles

Contact: claire.wilhelm@curie.fr

NANOPARTICLES BIO-TRANSFORMATIONS

With the growing medical use of magnetic nanoparticles, in particular for cell therapies, it is crucial to study their long-term intracellular fate within living tissues. We provided multiscale quantitative methods to study intracellular iron oxide nanoparticle degradation, showing an unexpected near-total nanoparticle degradation during long-term maturation of a stem cell model tissue. In brief, we developed stem cell spheroids as new biological tools to monitor intracellular nanoparticle degradation, and we managed to perform single spheroid magnetism in situ as a fingerprint of nanoscale transformations. Remarkably, and unexpectedly, the nanoparticles were found to be more than 90% purged inside the tissue in the first ten days of tissue maturation, barely affecting cellular iron homeostasis. The same massive degradation was recapitulated at the single endosome level, using a unique approach based on single purified endosome nano-magnetophoresis.

These results evidencing for the first time a total breakdown of nanoparticles by endosomes in stem cells composing a model tissue bodes well for their safety in medical applications, especially regenerative medicine.

Beyond its obvious nanosafety implications, the impact of the cellular environment on nanomaterials also raises concerns as to their therapeutic applicability, for either the tissue engineering field (long-term stimulation of engineered tissues), or for cancer therapies (serial treatments). It can thus be beneficial to protect iron oxide nanoparticles to massive intracellular dissolution.

We have showed that a gold shell can prevent the intracellular biodegradation of iron oxide nanoflowers and thereby maintain their potential for magnetic hyperthermia, in addition to the excellent photothermal efficiency of the gold shell itself. Besides, it demonstrates that not only magnetic metrics, but also thermal ones can be quantitative mirrors of the intracellular status.

Finally, we were the first to have just evidenced the possible biosynthesis of nanoparticles by human stem cells, using the ions delivered by the degradation of administered chemically synthesized nanoparticles.

SELECTION OF RECENT RELATED PUBLICATIONS

Massive Intracellular Remodeling of CuS Nanomaterials Produces Nontoxic Bioengineered Structures with Preserved Photothermal Potential. A Curcio, A Van de Walle, E Benassai, A Serrano, N Luciani, BB Manshian, A Sargsian, S Soenen, A Espinosa, A Abou-Hassan, C Wilhelm. ACS nano 15, 9782-9795 (2021)

Transformation Cycle of Magnetosomes in Human Stem Cells: From Degradation to Biosynthesis of Magnetic Nanoparticles Anew. Curcio A, Van de Walle A, Serrano A, Preveral S, Péchoux C, Pignol D, Menguy N, Lefèvre CT, Espinosa A, Wilhelm C. ACS nano 14, 1406-1417 (2020)

Ever-Evolving Identity of Magnetic Nanoparticles within Human Cells, the Interplay of Endosomal Confinement, Degradation, Storage, and Neo-Crystallization. Van de Walle A, Kolosnjaj-Tabi J, Lalatonne Y, Wilhelm C. Accounts of chemical research 53, 2212-2224 (2020)

Real-time in situ magnetic measurement of the intracellular biodegradation of iron oxide nanoparticles in a stem cell-spheroid tissue model. Van de Walle A, Fromain A, Plan Sangnier A, Curcio A, Lenglet L, Motte L, Lalatonne Y, Wilhelm C. Nano Research 13, 467-476 (2020)

Biosynthesis of magnetic nanoparticles from nano-degradation products revealed in human stem cells. Van de Walle A, Plan Sangnier A, Abou-Hassan A, Curcio A, Hémadi M, Menguy N, Lalatonne Y, Luciani N, Wilhelm C.  PNAS 116, 4044-4053 (2019) https://www.cnrs.fr/en/what-happens-magnetic-nanoparticles-once-cells  

Impact of magnetic nanoparticle surface coating on their long-term intracellular biodegradation in stem cells. Plan Sangnier A, Van de Walle A, Le Borgne R, Motte L, Lalatonne Y, Wilhelm C. Nanoscale, 11, 16488 (2019)

Intracellular Biodegradation of Ag Nanoparticles, Storage in Ferritin, and Protection by Au Shell for Enhanced Photothermal Therapy. Espinosa A, Curcio A, Cabana S, Radtke G, Bugnet M, Kolosnjaj-Tabi J, Péchoux C, Alvarez-Lorenzo C, Botton GA, Silva AKA, Abou-Hassan A, Wilhelm C. ACS nano 12, 6523–6535 (2018)

Magneto-Thermal Metrics Can Mirror the Long-Term Intracellular Fate of Magneto-Plasmonic Nanohybrids and Reveal the Remarkable Shielding Effect of Gold. Mazuel F, Espinosa A, Radtke G, Bugnet M, Neveu S, Lalatonne Y, Botton GA, Abou-Hassan A, Wilhelm C. Advanced Functional Materials, 27, 1605997 (2017)

Massive Intracellular Biodegradation of Iron Oxide Nanoparticles Evidenced Magnetically at Single Endosome and Tissue Levels. Mazuel F, Espinosa A, Luciani N, Reffay M, Le Borgne R, Motte L, Desboeufs K, Michel A, Pellegrino T, Lalatonne Y, Wilhelm C. ACS Nano, 10, 7627- 38 (2016)

EXTRACELLULAR VESICLES NANO-ENGINEERING

To deliver nanoparticles on-site, the last decades have seen the development of a variety of drug delivery systems. Recently, membrane-bound EVs released by cells, have emerged as a cell-to-cell communication system which could be used to bio-camouflage drugs.

We pioneered this possibility to load EVs with NPs and drugs, by incorporating them in the parent cells prior to trigger vesicles emission. To make such bio-camouflaged NPs a reality for clinical applications, the community must solve production and low loading issues. We showed for instance that an hydrodynamic stimulation can increase the number of EVs (10 times more in 10 times less time), as well as the loading of a drug, and that a laser stimulation (activating a photosensitizer) can also increase EVs production.

SELECTION OF RECENT RELATED PUBLICATIONS

Massive release of extracellular vesicles from cancer cells after photodynamic treatment or chemotherapy. Aubertin K, Silva AKA, Luciani N, Espinosa A, Djemat A, Charue D, Gallet F, Blanc-Brude O, Wilhelm C. Scientific Reports, 6, 35376 (2016)

Combining magnetic nanoparticles with cell derived microvesicles for drug loading and targeting. Silva AKA, Luciani N, Gazeau F, Aubertin K, Bonneau S, Chauvierre C, Letourneur D, Wilhelm C. Nanomedicine NBM, 11, 645–655 (2015)

Cell-derived Vesicles as a Bioplatform for the Encapsulation of Theranostic Nanomaterials. Silva AKA, Di Corato R, Luciani N, Chat S, Gazeau F, Pellegrino T, Wilhelm C. Nanoscale. 7, 11374-84 (2013)

Magnetic and photoresponsive theranosomes: translating cell-released vesicles into smart nanovectors for cancer therapy. Andriola A, Kolosnjaj J, Bonneau S, Marangon I , Bogetto N, Aubertin K, Clément O, Bureau MF, Luciani N, Gazeau F, Wilhelm C.  ACS nano 7, 4954–4966 (2013)