Principal Investigator and Contact : Stéphanie Descroix, Stephanie.Descroix@curie.fr

One of the strong motivations of the team since its creation has been the development of tools directly useful for the biology and clinics, helped and stimulated in that by the unique environment provided by Curie Institute. The new team will continue along this vocation in particular in the field of droplet microfluidics for single cell analysis, drug screening, chemical sensing or for EVs characterization.

Principal Investigator and Contact : Stéphanie Descroix, Stephanie.Descroix@curie.fr

Bioengineering models that faithfully recapitulate in vitro organ features remains a challenging task; it is however needed in several fields: first to provide damaged tissue replacements for regenerative medicine, but also for drug assessments and advanced biological and biophysical investigations. Since its inception, 3D bioengineering has made significant progress towards the goal of functional tissue production notably thanks to organ on chip technology. However, many efforts must still be made to properly differentiate cells and promote faithful tissue development and organization in microphysiological systems. This is particularly linked to the need to recapitulate both the 3D organ structure, the intercellular organization, and the mechanical stimulation experienced in vivo, in order to finally promote a functional tissue.

We have recently demonstrated our ability to develop original and relevant organ on chip models. Building on this know-how along with our expertise in magnetic cellular material we aim now at initiating a novel research methodology in the field of 3D bioengineering with a tuned balance between structural and magnetic cellular and extracellular components.

Principal Investigator and Contact : Stéphanie Descroix, Stephanie.Descroix@curie.fr

A critical problem in the development and deployment of effective anti-cancer treatments is the lack of adequate in-vitro model systems and this is particularly true for combined therapies. Conventional cell cultures or animal models (such as nude mice for patient-derived xenograft) fail to accurately predict drug responses in humans as they do not properly mimic the complexity of human physiopathology, particularly the immune tumor-microenvironment; for instance, nude mice are severely immuno-compromised to allow human xenografting. This is why clinical trial success rate in oncology is dramatically low. The use of animal models also raises ethical problems regarding animal well-being especially in the 3R context.

Hence, there is an urgent need to develop new technologies that allow investigating the effect of anti-cancer therapies in particular when used in combination by being able to assess their influence on the tumor microenvironment as well as by controlling the composition of these humanized cellular tumor ecosystems for both research and treatment purposes. In the last decade, basic research showed how our understanding of the behavior of physiological and patho-physiological systems can be greatly increased thanks to a rational simplification of the human body in artificial microsystems. Microtechnology and specifically microfluidics, provided powerful tools, to interact with cells at their own scale, tailoring the artificial microenvironment on experimental needs. In this context, we have initiated a strong collaboration with the team of F. Mechta-Gregoriou at Institut Curie in particular with MC Parrini, G. Zalcman and J. Camonis to develop relevant in vitro microphysiological models of tumor microenvironment. We aim at pursuing in this research direction through both biological and biophysical approaches.

Despite already promising results, we still consider that our tumor on chip (ToC) platform could be further improved. In particular, we aim at integrating functional vessels on chip. Besides, in collaboration with Fluigent company, we also aim at implementing a new generation of ToC with a fine control of physioxic or hypoxic conditions.  Those improvements will both improve the completion of ToC biomimetism and allow for a better understanding of TME response to different drugs. With the team of F. Mechta-Gregoriou, we are currently implementing the on-chip reconstitution a simplified immunocompetent lung tumor microenvironment to quantify the effects of immune checkpoint inhibitor on the tumor ecosystem. We will use these models to dissect the response of the tumour microenvironment to therapeutic approaches combining nanoparticle-mediated hyperthermia and chemotherapy or immunotherapy.

In parallel, we also aim at further probing the biophysical properties of reconstituted tumor.  More specifically, tumor magnetic spheroid can be used as both rheological probes and biological actors of the tumor microenvironment. They can be either compressed in magnetic field gradient to measure in-depth rheological properties of these tumors-to-be or they can be manipulated by magnetic attractors within chips to probe the rheological properties of their environment to assess the effect of chemo- or photo-therapies on TME biophysical properties. Importantly, because these approaches involve the incorporation of exogenous nanoparticles in cells, we will also focus on the biological fate of these nanoparticles within the engineered tissues, and investigate their assimilation after playing their initial role as magnetic organizers and stimulators

Principal Investigator and Contact : Claire Wilhelm, claire.wilhelm@curie.fr

Cell therapies and medically oriented nanotechnologies are currently among promising biotechnologies. One attractive approach is to associate magnetic nanoparticles with cells in order to supply them with sufficient magnetization to be detectable by MRI, manipulated by magnetic forces, or treated with therapeutic hyperthermia.

We are exploring nanoparticles internalization in (human stem) cells. We investigate how intracellular magnetic nanoparticles allow applications of tissue engineering mediated by cellular magnetic force to mimic the most closely multicellular organisations found in the living. The aim is to confine cells in three dimensions at the millimetric scale by using home-designed miniaturized magnetic devices, in order to create cellular patterns for stem cell differentiation and tissue engineering.

1. Magnetic tissue stretcher

We are developing a magnetic tissue stretcher which provides a versatile tissue stimulator: frequency, longitudinal extension, speed of displacement and force amplitude can be varied at will. A 750 µm diameter soft iron tip magnetized either by a permanent magnet is first used to form a cell aggregate. A second identical tip is then approached. With the permanent magnet, the aggregate is rapidly deformed into a rectangular shape, and stretched when the second tip is drawn away. 

Such stretching and compression capacity is particularly suited to cardiac and skeletal muscle geometry. For cardiac stimulation, a cyclic stretching was imposed, and resulted in almost total differentiation of embryonic mouse stem cells to cardiomyocytes.

2. Magnetic molding of multicellular aggregates (spheroids)

Current limitations in standard techniques for spheroid formation persist and limit their applicability, like low degree of sphericity, poor control of spheroid size and long maturation times. We implement and reported a fast and highly reproducible spheroid generation technique to address these limitations based on the labeling of cells with magnetic nanoparticles and their subsequent aggregation by means of an external magnet.

3. Scale-up of magnetic spheroid formation and stimulation

Scalable Ni-based magnetic micropattern are developed for spheroid formation and stimulation. It provides a unique all-in-one solution to both create hundreds of spheroids, for instance made of embryoïd stem cells (embryoïd bodies) with no direct contact and no supporting matrix, in a high-throughput manner, and to stimulate them mechanically in situ (with electromagnet), in an on/off cyclical manner that mimics cardiac muscle contraction. It was sufficient to guide almost all embryoïd bodies towards the cardiac lineage commitment, a feat that was not reached with other approaches of embryoïd bodies differentiation.

4. Magnetic cells aligner

Another technique based on remote magnetic cell actuation is developed to align magnetically labeled cells in hydrogel. Remarkably, the hydrogel viscosity, before gel transition, allowed multilayer cell formation of aligned cell structures, at centimeter scale. The key stage then consist in exploiting gel transition to stabilize the pattern and create aligned, functional and viable tissues. Importantly, this strategy can be implemented without the need for external mechanical cues (no molds, frames nor posts). Instead, magnetic actuation provided high precision and accuracy for spatial and temporal pattern control.

5. Magnetic tissue rheometer

Finally, cells magnetization also allows developing a unique all-in-one rheometer by first forming a multicellular aggregates of controlled cylindrical shape, and then applying a precise magnetic compression at the tissue scale, to retrieve the rheological properties of the construct.

SELECTION OF RECENT RELATED PUBLICATIONS

Transient cell stiffening triggered by magnetic nanoparticle exposure. JE Perez, F Fage, D Pereira, A Abou-Hassan, S Asnacios, A Asnacios, C Wilhelm. Journal of Nanobiotechnology 19, 1-13 (2021)

Magnetic molding of tumor spheroids: Emerging model for cancer screening. Perez JE, Nagle, I, Wilhelm C. Biofabrication 13, 015018 (2020)

High‐Throughput Differentiation of Embryonic Stem Cells into Cardiomyocytes with a Microfabricated Magnetic Pattern and Cyclic Stimulation. Mary G, Van de Walle A, Perez JE, Ukai T, Maekawa T, Luciani N, Wilhelm C. Advanced Functional Materials 12002541 (2020)

A 3D magnetic tissue stretcher for remote mechanical control of embryonic stem cell differentiation. Du V, Luciani N, Richard S, Mary G, Gay C, Mazuel F, Reffay M, Menasché P, Agbulut O, Wilhelm C. Nature Communications, 8, 400 (2017) http://www2.cnrs.fr/presse/communique/5181.htm?theme1=4

Magnetic flattening of stem-cell spheroids indicates a size-dependent elastocapillary transition.
Mazuel F, Reffay M, Du V, Bacri J-C, Rieu J-P, Wilhelm C. Phys Rev Lett, 114, 098105 (2015).
Magnetic engineering of stable rod-shaped stem cell aggregates: circumventing the pitfall of self-bending. Fayol D, Du V, Reffay M, Luciani N, Bacri J-C, Gay C, Wilhelm C. Integrative Biology, 7, 170-177 (2015)

Magnetic forces promote stem cell differentiation, aggregates fusion and tissue building. Fayol D, Frasca G, Le Visage C, Gazeau F, Luciani N, Wilhelm C. Advanced Materials. 25, 2611-2616 (2013)

Contact: claire.wilhelm@curie.fr

To combat cancer with early detection and treatment, new strategies have emerged thanks to the development of nanomaterials exhibiting new properties stemming from the reduction of their size. One major mission of these nanomaterials is the promise to bring nano-physical therapies on target tissues, with precise temporal and spatial control of the therapeutic action, together with low side effects. These nano-physical therapies are mediated by nanoparticles cores that can be excited by a remote energy source (light, magnetism or radiation), and generate in turn a physical effect, such as heat, force, or field. In this context, we have been investigating the efficiency of magnetic hyperthermia, photothermia, and photodynamic therapy for cancer therapies, with the final aim to combine one with the other, for enhanced treatments at low nanoparticles doses.

Concerning thermal therapies, state-of-the-art modalities are the magnetic hyperthermia and the photothermal ones. Yet, for both, main limitations are the important doses of nanoparticles needed to achieve a therapeutic heating. Thus, the obvious question comes to mind: why not combine the two heat sources - magnetic and plasmonic - to enhance heating efficiency? We introduced this magneto-photo-thermal modality with magneto-plasmonic hybrids, or with iron oxide nanoparticles only. Indeed, we demonstrated that photothermia with magnetic nanoparticles could be proposed as an alternate to magnetic hyperthermia.

While the ultimate target for nanoparticle-mediated photothermal therapy is the cancer cell, heating performance has rarely been evaluated in cancer cells in vitro, or in vivo in the tumor environment.

In the attempt to bridge this gap, we provided magnetic hyperthermia measurements in the cellular environment and photothermal measurements of plasmonic nanoparticles in environments of increasing biological complexity, from aqueous dispersion to solid tumors, via tumor cells in vitro.

SELECTION OF RECENT RELATED PUBLICATIONS

Janus magnetic-plasmonic nanoparticles for magnetically guided and thermally activated cancer therapy. Espinosa A, Reguera J, Curcio A, Muñoz A, Van de Walle A, Liz-Marzán L, Wilhelm C. Small 16 1904960 (2020)

Endosomal confinement of gold nanospheres, nanorods and nanoraspberries governs their photothermal identity and is beneficial for cancer cells therapy. Plan Sangnier A, Van de Walle A, Motte L, Guenin E, Lalatonne Y, Wilhelm C. Advanced Biosystems 4, 1900284 (2020)

Raspberry-like small multicore gold nanostructures for efficient photothermal conversion in the first and second near-infrared windows. Plan Sangnier A, Aufaure R, Cheong S, Motte L, Palpant B, Tilley RD, Guenin E, Wilhelm C*, Lalatonne Y*. Chemical Communications, 55, 4055-4058 (2019)

Iron Oxide Nanoflowers @ CuS Hybrids for Cancer Tri-Therapy: Interplay of Photothermal Therapy, Magnetic Hyperthermia and Photodynamic Therapy. Curcio A, Silva AKA, Cabano S, Espinosa A, Baptiste B, Menguy N, Wilhelm C*, Abou-Hassan A*. Theranostics, 9, 1288-1302 (2019)

Magnetic (hyper)thermia or photo-thermia? Progressive comparison of iron oxide and gold nanoparticles heating in water, in cells, and in vivo. Espinosa A, Kolosnjaj-Tabi J, Abou-Hassan A, Plan Sangnier A, Curcio A, Silva AKA, Di Corato R, Neveu S, Pellegrino T, Liz-Marzán LM, Wilhelm C. Advanced Functional Materials 1803660 (2018)

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)

Targeted thermal therapy with genetically engineered magnetite magnetosomes@RGD: Photothermia is far more efficient than magnetic hyperthermia. Plan A, Preveral S, Curcio A, Silva A, Lefèvre CT, Pignol D, Lalatonne Y, Wilhelm C. Journal of Controlled Release 279, 271-281 (2018)

Duality of Iron Oxide Nanoparticles in Cancer Therapy: Amplification of Heating Efficiency by Magnetic Hyperthermia and Photothermal Bimodal Treatment Espinosa A, Di Corato R, Kolosnjaj-Tabi J, Flaud P, Pellegrino T, Wilhelm C. ACS Nano, 10, 2436-46 (2016)

Cancer cell internalisation of gold nanostars impacts their photothermal efficiency in vitro and in vivo: towards a plasmonic thermal fingerprint in tumoral environment Espinosa A, Silva AKA, Sánchez-Iglesias A, Grzelczak M, Péchoux C, Desboeufs K, Liz-Marzán LM, Wilhelm C. Advanced HealthCare Materials, 5, 1040- 48 (2016)

Combining magnetic hyperthermia and photodynamic therapy for tumor ablation with photoresponsive magnetic liposomes. Di Corato R, Béalle G, Kolosnjaj-Tabi J, Espinosa A, Clément O, Silva AKA, Ménager C, Wilhelm C. ACS Nano, 9, 2904-2916 (2015) http://www2.cnrs.fr/presse/communique/3969.htm

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)

Comment une cellule unique donne-t-elle naissance à un organisme ? Louise nous aide à comprendre dans cette vidéo :

Début mars, doctorants, post-doctorants et chercheurs de l’équipe MMBM ont eu la chance de passer quelques jours dans le centre CNRS d’Aussois, en Savoie. Lors du séjour, nous avons échangé sur les projets effectués au sein de l’équipe sous la forme de jeux et d’exercices de partage tels que pitcher en 180 secondes le sujet de recherche d’un collègue. Nous avons également travaillé sur de nouvelles pratiques de laboratoire plus robustes. Enfin, afin de profiter des magnifiques paysages de la région, un guide nous a emmené randonner et découvrir les bouquetins du parc de la vanoise. C’était une très belle semaine pour se ressourcer et être ensemble.

L'équipe NanoBioMag animée par Claire Wilhelm se situe depuis toujours à l’interface de la biophysique, de la science des matériaux et de la nanomédecine. L’objectif principal est de réussir à fournir l'image la plus complète possible des modes d'action et du devenir de nanoparticules (le plus souvent magnétiques) dans leurs environnements biologiques cibles. Le premier volet a été financé par l'ANR (MagStem) en 2010, l'ERC (MaTissE) en 2014 et l'ANR (SuperMagStemCells) en 2019, et a conduit au développement de méthodes basées sur le magnétisme pour manipuler les cellules vivantes, explorer la mécanique des tissus, et fournir des substituts de tissus magnétisables. Le second volet a été financé par l’Europe (FP7) en 2012 (Magnyfico) et l’ERC (NanoBioMade) en 2019 et a proposé des thérapies anticancéreuses combinées en appliquant plusieurs stimuli sur de mêmes nanoparticules, démontrant par exemple pour la première fois que des nanoparticules magnétiques pouvaient être des agents photo-thermiques efficaces. Il reste alors à savoir si et comment les propriétés des nanoparticules peuvent évoluer une fois leur mission thérapeutique accomplie, au cœur de leurs cibles cellulaires ou dans l'organisme. De plus, ces mêmes nanoparticules peuvent être transportées et bio-camouflées dans des vésicules extracellulaires.

NanoBioMag Works 1: Magnetic Tissue Bioengineering.

NanoBioMag Works 2 : Nano-Therapies.

NanoBioMag Works 3 : Nanoparticles fate and transport in extracellular vesicles.

NanoBioMag Projects 1 : Biogenic photo-responsive vectors in nanomedicine.

NanoBioMag Projects 2 : Magnetic tissue stretcher.

MEMBRES NanoBioMag

• Claire Wilhelm, directrice de recherche CNRS DR1
• Aurore Van de Walle, chercheuse CNRS
• Jose Efrain Perez, chercheur postdoctorant
• Noam Demri, PhD student (co-direction Stéphanie Descroix)
• Elliot Thouvenot, PhD student (co-direction Amanda Silva Brun)
• Caroline Parent, PhD student (co-direction Jean-Louis Viovy)
• Guilhem Curé, PhD student (co-direction Aurore Van de Walle)
• Solène Lenoir, assistante-ingénieure

ALUMNI NanoBioMag

• Irène Nagle, PhD 2023, co-direction Myriam Reffay
• Alexandre Fromain, PhD 2022
• Alice Grangier, PhD 2022, co-direction Amanda Silva Brun
• Anouchka Plan Sangnier, 2019, co-direction Yoann Lalatonne
• Gaëtan Mary, PhD 2019, co-direction Myriam Reffay
• Alberto Curcio, chercheur postdoctorant 2016-2020
• Aurore Van de Walle, chercheuse postdoctorante 2015-2018
• François Mazuel, PhD 2016
• Vicard Du, PhD 2015
• Ana Espinosa, chercheuse postdoctorante 2013-2017
• Sophie Richard, chercheuse postdoctorante 2016-2017
• Kelly Aubertin, PhD 2014
• Riccardo Di Corato, chercheur postdoctorant 2011-2013
• Amanda Silva Brun, chercheuse postdoctorante 2010-2013
• Delphine Fayol, PhD 2012
• Michael Lévy, PhD 2011, co-direction Florence Gazeau
• Damien Robert, PhD 2010
• Guillaume Frasca, PhD 2010

CONTACT : Claire Wilhelm; claire.wilhelm@curie.fr

Cells can profoundly transform and recycle man-made nanomaterials, to which they had been exposed.  To communicate, or in response to exogenous stress, cells generate extracellular vesicles (EVs) which can play crucial roles in multiple physiological processes, including cancer progression. The goal of this project is to combine both biological processes to deliver cell-made nanomedicines.

First, we are developing novel strategies to induce bioinorganic intracellular synthesis of nanoparticles (NPs). This demonstrate that i) NP degradation products can be de novo-synthesized NPs and ii) NPs can also be obtained when cells are “fed” with soluble ionic salts. Using living cells as bioreactors may create functional, complex and organism-friendly NPs.

The second goal is devoted to the biological encapsulation of NPs. For clinical applications, NPs must be efficiently delivered to the target site. The best delivery system is the cell’s innate one, the EVs. Here, ground-breaking physically inspired (hydrodynamic, light) approaches are proposed and implemented to produce and load EVs with NPs. One specific aim will be to scale-up the production and loading.

The last objective is to exploit biosynthesized NPs and their bio-camouflage within EVs as photothermal agents, used in thermal treatments of cancer. A panel of magnetic nanomaterials, nano-bio-hybrids, vesicles, combination of vesicles and liposomes, are magnetically or chemotactically delivered to tumour models, where their action would be triggered by light stimuli to treat cancer.

FUNDING: ERC-CoG-2019 NanoBioMade

PARTICIPANTS: Claire Wilhelm CNRS DR1, Aurore Van de Walle CNRS CRCN, Elliot Thouvenot PhD student, Guilhem Curé PhD student.

CONTACT : Claire Wilhelm; claire.wilhelm@curie.fr

The rationale is to safely introduce magnetic nanoparticles in cells, mostly cardiac and skeletic muscle cells, thus allowing them to be remotely manipulated by external magnets.  In a self-integrating all-in-one process, we are thus currently developping magnetic tissues amenable to mechanical stimulation and in situ imaging at each step of  the maturation. By combining magnetic cell micropatterning and stretching. it provides a versatile tissue stimulator.

FUNDING: ERC-CoG-2014 MaTissE; ANR SuperMagStemCells

PARTICIPANTS: Noam Demri, PhD student; Giacomo Gropplero, engineer; Efrain Jose Perez, postdoctoral fellow; Simon Dumas, postdoctoral fellow; Stéphanie Descroix, CNRS DR1; Claire Wilhelm, CNRS DR1.