Sujets

Statistical mechanics approaches to understand chemical processes in complex environments, from materials to **biomolecules**.

Mass spectrometry methods for studying biomolecule interactions and post-translational modifications.

Solid-state NMR methods for studying living microorganisms and biological systems.

Development of novel fluorescent biosensors and chemical-genetic tools for live-cell imaging.

Investigation of peptide-membrane interactions, cell-penetrating peptides, and antimicrobial peptides.

In line with the team’s ambition to develop innovative tools for manipulating biological systems, our research focuses on the design of responsive macromolecules based on comb-like copolymers. On one hand, these polymers are used to engineer stimuli-responsive coatings that enable control over cell adhesion, with current efforts emphasizing light as an external trigger (F. Dalier, ACS Applied Materials & Interfaces, 2018; G. Boniello, Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2019). On the other hand, they are employed in the design of responsive capsules aimed at achieving spatiotemporal control over drug delivery to trigger specific cellular events (L Sixdenier, ACS Macro Letters, 2022; L Sixdenier, The Journal of Physical Chemistry Letters, 2023).

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### Chemogenetic tools to observe cell biology at various scale in space and time Fluorescent reporters and sensors play a central role in biological and medical research. Targeted to specific biomolecules or cells, they allow the visualization of the mechanisms that govern cells and organisms in real time. Recently, chemogenetic reporters composed of organic chromophores interacting with a protein moiety have challenged the hegemony of fluorescent proteins classically used in Cell Biology. Combining the advantage of synthetic fluorophores with the targeting selectivity of genetically encoded systems, these chemogenetic reporters open new perspectives for the study of cellular processes. Our team has recently introduced a new class of chemogenetic fluorescent reporters, called FASTs (fluorescence-activating and absorption-shifting tags), which allow the visualization of gene expression and protein localization in living cells and organisms (PNAS 2016, Chem. Sci. 2017, Bioconjug. Chem. 2018, Angew. Chem. 2020, Nat. Chem. Biol. 2021, Nat. Commun. 2021, Acc. Chem. Res. 2022). Engineered using a concerted strategy of molecular engineering and directed protein evolution, FASTs are small protein tags that bind and stabilize the fluorescent state of fluorogenic chromophores. Dark when free in solution or cells, these so-called fluorogens allow the imaging of FAST-tagged proteins with very high contrast without the need for washing. FAST and its variants have proved to be a useful tool that is compatible with multiple microscopy modalities and model organisms. It excels in applications in oxygen-poor environments or in situations where the lack of delay in the formation of a fluorescent complex allows the detection of rapid biological events. Recently, we expanded our toolbox with near-infrared chemogenetic fluorescent reporters (Nat. Commun. 2025) for advanced in vivo imaging and fluorescence lifetime-modulating tags for highly multiplexed imaging in cells and organisms (Advanced Science 2024). The modular nature of these reporters allowed us furthermore to design biosensors for the detection of key metabolites (ACS Chem. Biol 2018, ACS Sensors 2023). In addition, bisection of FASTs into two complementary fragments enabled the design of split fluorescent reporters with rapid and reversible complementation for the imaging of dynamic protein-protein interactions (Nat. Commun. 2019, ACS Chem. Biol. 2024, ChemBioChem 2025). This latter technology holds great potential for developing screening strategies to identify stabilizers or disruptors of protein-protein interactions, which could have therapeutic applications. Recently, splitFAST has been successfully employed to probe the dynamics of membrane contact sites (Nat. Commun. 2024) and has been extended to a tripartite version for the detection of ternary interactions (Nat. Commun. 2025), further expanding its versatility and utility in biological research. Our current research interests focus on: 1. innovative chemogenetic optical reporters and sensors for imaging cell biology at various scale in space and time using advanced microscopy. 2. generic tools to image endogenous proteins to systematically study protein function in a native cellular background. 3. optical sensors of protein-protein, organelle-organelle, and cell-cell interactions. 4. optical mechanosensors for measuring forces in cells. ### Chemogenetic tools to control cellular functions in cell biology and biomedicine The specificity of cellular functions results from the spatial and temporal organization of functionally interacting proteins. Various strategies are used by cells to achieve specificity including protein compartmentalization in organelles, protein colocalization on membranes, or assembly of protein complexes mediated by specific scaffolds. Such spatial organization enables to increase effective molarity in biochemical processes and is essential for key cellular processes such as gene regulation, protein transport, organelle transport and positioning, signal transduction, metabolism, immune response or cell-cell communications. To study and understand the role of the spatiotemporal organization of proteins in these processes, we recently introduced CATCHFIRE (Chemically Assisted Tethering of CHimera by Fluorogenic Induced Recognition), a chemogenetic tool enabling to control the physical proximity of proteins and quantify this proximity (Nat. Methods 2023). This tool relies on the genetic fusion of two small dimerization domains that can interact together in presence of a fluorogenic inducer of dimerization that fluoresces upon formation of the ternary assembly, allowing real-time monitoring of chemically induced proximity. This technology allows the fine control of biological processes through chemically induced proximity of proteins. Our current research interests focus on: 1. Chemically induced proximity tools to manipulate and control biochemical processes for cell biology applications. 2. Small-molecule-based control modules for applications in cell biology and cell therapy.

Our team specializes in the development of cutting-edge chemical tools to enable high-precision biological imaging. By integrating expertise in chemical biology, organic synthesis, and photophysics, we design and optimize small molecule probes that push the boundaries of live-cell and super-resolution microscopy. ### Key Research Areas #### Fluorogenic Bioorthogonal Reactions for Biomolecule Labeling Bioorthogonal chemistry allows the selective labeling of biomolecules in complex biological environments. Our team is pioneering the development of fluorogenic bioorthogonal reactions, where two non-fluorescent reagents react to form a fluorescent product. This approach ensures high contrast and spatiotemporal precision in labeling, eliminating background fluorescence and enabling real-time imaging without washing steps. Our work focuses on expanding the toolkit for near-infrared probes and improving the quantification of reaction efficiency, with broad applications in live-cell imaging. #### Blinking Dyes for Super-Resolution Microscopy Super-resolution microscopy has transformed our ability to visualize cellular structures at the nanoscale. We are developing blinking dyes based on the BODIPY scaffold, which exhibit exceptional photophysical properties, including high quantum yields, narrow emission bands, and low toxicity. By fine-tuning their structure, we control their on/off equilibrium, making them ideal for single-molecule localization microscopy (SMLM). This technique enables nanometric precision in imaging, providing unprecedented insights into cellular organization and dynamics. ### Our Approach - Innovative Synthesis: Design and synthesis of novel fluorescent probes tailored for specific imaging applications. - Photophysical Optimization: Tuning probe properties to enhance contrast, stability, and compatibility with live-cell environments. - Biological Validation: Characterization of probes in physiological conditions to ensure reliability and performance.

Fluorescence imaging is widely used in the life sciences to study biological processes, most often with exogenous fluorescent probes. However, the illumination required to excite these probes also induces photochemical reactions whose mechanisms are often poorly understood. A rigorous understanding of probe photochemistry is essential for their proper use in imaging, for controlling photochemical reactions, and for improving probe design. Since the advent of super-resolution microscopy, probe photochemistry has also been a continuous source of inspiration for the development of innovative imaging methods. Our work on fluorescent probes therefore combines fundamental mechanistic studies with methodological developments in imaging. Recent work has focused on fluorescent proteins of the GFP family, which are the main probes used for in vivo imaging. ### 1. Reverse Intersystem Crossing to Reduce Photobleaching and Phototoxicity Photobleaching and phototoxicity are among the principal limitations of fluorescence imaging. Both processes are generally understood to involve the triplet excited states of fluorescent probes as key intermediates. We recently introduced a method to reduce photobleaching of fluorescent proteins and the associated phototoxicity in vivo under wide-field illumination (Ludvikova *et al.*, *Nature Biotechnology*, 2024). This approach exploits reverse intersystem crossing (RISC) to depopulate triplet states using near-infrared light. The method can be readily implemented on commercial wide-field microscopes and is effective in both eukaryotic and prokaryotic cells for a broad range of green and yellow fluorescent proteins. Ongoing work aims to extend this strategy to other classes of fluorophores and imaging modalities.  ### 2. Mechanisms of Fluorescent Protein Photoswitching Reversibly photoswitchable fluorescent proteins (RSFPs) are central probes in super-resolution microscopy and other advanced imaging techniques. X-ray crystallography has revealed two possible photoswitching mechanisms: cis–trans isomerisation of the chromophore coupled to proton transfer, or the reversible addition of a water molecule to the chromophore. We have characterised these two mechanisms in detail using time-resolved spectroscopy down to the femtosecond timescale, focusing on the RSFPs Dreiklang (Renouard *et al.*, *J. Phys. Chem. Lett.*, 2023; Lacombat *et al.*, *J. Phys. Chem. Lett.*, 2017) and Dronpa (Yadav *et al.*, *J. Phys. Chem. B*, 2015). This work has enabled us to establish a comprehensive mechanistic picture of the elementary steps and characteristic time scales governing fluorescent protein photoswitching. ### Experimental Capabilities We are equipped for mechanistic photochemistry studies with a home-built femtosecond transient absorption spectroscopy setup (excitation 300–700 nm, broadband probe 300–1100 nm, time window 100 fs–3 ns) and a nanosecond optical parametric oscillator (excitation 190–2500 nm) for time-resolved fluorescence and micro- to millisecond transient absorption measurements. These instruments are also routinely used in collaborative projects to investigate molecular systems beyond fluorescent proteins. ### Selected References - **Near-infrared co-illumination of fluorescent proteins reduces photobleaching and phototoxicity**, L. Ludvikova, E. Simon, M. Deygas, T. Panier, M.-A. Plamont, J. Ollion, A. Tebo, M. Piel, L. Jullien, L. Robert, T. Le Saux, A. Espagne, *Nature Biotechnology*, 2024, **42**, 872–876. [Link] - **Multiscale transient absorption study of the fluorescent protein Dreiklang and two point variants provides insight into photoswitching and non-productive reaction pathways**, E. Renouard, M. Nowinska, F. Lacombat, P. Plaza, P. Müller, A. Espagne, *The Journal of Physical Chemistry Letters*, 2023, **14**, 6477–6485. [Link] - **Ultrafast oxidation of a tyrosine by proton-coupled electron transfer promotes light activation of an animal-like cryptochrome**, F. Lacombat, A. Espagne, N. Dozova, P. Plaza, P. Müller, K. Brettel, S. Franz-Badur, L.-O. Essen, *Journal of the American Chemical Society*, 2019, **141**, 13394–13409. [Link] - **Photosensitized oxidative addition to gold(I) enables alkynylative cyclization of o-alkylnylphenols with iodoalkynes**, Z. Xia, V. Corcé, F. Zhao, C. Przybylski, A. Espagne, L. Jullien, T. Le Saux, Y. Gimbert, H. Dossmann, V. Mouriès-Mansuy, C. Ollivier, L. Fensterbank, *Nature Chemistry*, 2019, **11**, 797–805. [Link] - **Photoinduced chromophore hydration in the fluorescent protein Dreiklang is triggered by ultrafast excited-state proton transfer coupled to a low-frequency vibration**, F. Lacombat, P. Plaza, M.-A. Plamont, A. Espagne, *The Journal of Physical Chemistry Letters*, 2017, **8**, 1489–1495. [Link] - **Real-time monitoring of chromophore isomerization and deprotonation during the photoactivation of the fluorescent protein Dronpa**, D. Yadav, F. Lacombat, N. Dozova, F. Rappaport, P. Plaza, A. Espagne, *The Journal of Physical Chemistry B*, 2015, **119**, 2404–2414. [Link]

When practiced at its interface with biology and physics, chemistry offers more than a toolkit for labeling biomolecules or analyzing cellular composition. It provides a distinct molecular perspective that enables quantitative interrogation of interactions and kinetic analysis of exquisitely complex reaction networks. This perspective underlies our research activity: we introduce and implement chemical concepts and tools to interrogate and manipulate biological systems. More specifically, our recent work focuses on the development of photoactive organic probes and reactivity-based protocols for highly selective analyses and imaging in live cells as well as in photosynthetic organisms (microalgae and plants). ### Recent References - R. Chouket, A. Pellissier-Tanon, A. Lahlou, R. Zhang, D. Kim, M.-A. Plamont, M. Zhang, X. Zhang, P. Xu, N. Desprat, D. Bourgeois, A. Espagne, A. Lemarchand, T. Le Saux, L. Jullien, **Extra kinetic dimensions for label discrimination**, *Nature Communications*, 2022, **13**, 1482. - A. Lahlou, H. Sepasi Tehrani, I. Coghill, Y. Shpinov, M. Mandal, M.-A. Plamont, I. Aujard, Y. Niu, L. Nedbal, D. Lazár, P. Mahou, W. Supatto, E. Beaurepaire, I. Eisenmann, N. Desprat, V. Croquette, R. Jeanneret, T. Le Saux, L. Jullien, *Nature Methods*, 2023, **20**(12), 1930–1938. - H. Merceron, I. Coghill, A. Lahlou, M.-A. Plamont, L. Jullien, T. Le Saux, **Periodic Light Modulations for Low-Cost Wide-Field Imaging of Luminescence Kinetics Under Ambient Light**, *Advanced Science*, 2025, **12**(10), 2413291. - H. Merceron, E. Israelievitch, V. Rollot, T. Villarubias, X. Xie, T. Le Saux, K. Benzerara, F. Guyot, A. Boulouis, E. Marie-Bègue, L. Thouin, L. Jullien, **A Reaction–Diffusion Frame for Accessing Metabolic O₂ Fluxes in Single Microalgal Cells with Low-Cost Wide-Field Imaging of Nanosensor Luminescence Lifetime**, *Advanced Science*, 2025, **12**(42), e10903. - Y. Shpinov, M. Mandal, V. van Deuren, A. Lahlou, M. Le Bec, R. Chouket, C. Hadj Moussa, C. Bonin, H. Sepasi Tehrani, I. Coghill, L. El Hajji, K. Ounoughi, J. Franco Pinto, M.-A. Plamont, P. Pelupessy, I. Ayala, F. Perez, I. Aujard, T. Le Saux, A. Gautier, P. Dedecker, B. Brutscher, L. Jullien, **Photoejection turns non-covalent fluorescent tags into negative reversible photoswitchers**, *bioRxiv*, 2025, doi: 10.1101/2025.12.05.692574.

### 1. New Tools to Study Phase Separation in Living Cells Biomolecular condensates formed by intracellular phase separation organize essential cellular processes, from gene regulation to metabolism. While phase separation is now recognized as a key organizing principle, the rules governing condensate composition, dynamics, and function remain poorly understood. To address this, we develop engineered artificial scaffolds that form phase-separated condensates directly in living cells (Cochard et al., *EMBO J.* 2023; *Biophys. J.* 2022). This bottom-up approach enables precise control of condensate properties within the native cellular environment, allowing us to engineer new cellular functions and model pathological condensates linked to aging and disease. ### 2. Harnessing Biochemical Processes with Synthetic Condensates Cellular compartmentalization relies on dynamic exchange between organelles, yet existing perturbation methods lack specificity and control. We developed **ControLD**, a strategy to physically isolate lipid droplets—key organelles in energy storage and stress protection (Amari et al., *Nat. Chem. Biol.* 2025). ControLD uses engineered phase-separating proteins to form a reversible meshwork on lipid droplets, selectively blocking their metabolism and enabling direct interrogation of organelle communication. ### 3. Biophysics of Proteinopathies in Neurodegeneration and Cancer Many neurodegenerative diseases arise from the conversion of soluble proteins into pathological aggregates, including α-synuclein, TAU, and TDP-43. How these aggregates drive cellular dysfunction remains unclear. We develop cellular models of disease-relevant condensates and aggregation. Recently, we showed that spreading α-synuclein aggregates convert liquid α-synuclein condensates into amyloids (Piroska et al., 2025), providing a controlled system to study pathogenic aggregation mechanisms. ### Recent References - Cochard A., Safieddine A., Combe P., Benassy M.-N., Weil D., Gueroui Z., **Condensate functionalization with motors directs their nucleation in space and allows manipulating RNA localization**, *The EMBO Journal*, 2023. https://doi.org/10.15252/embj.2023114106 - Cochard A., Garcia-Jove Navarro M., Kashida S., Kress M., Weil D., Gueroui Z., **RNA at the surface of phase-separated condensates impacts their size and number**, *Biophysical Journal*, 2022. https://doi.org/10.1016/j.bpj.2022.03.032 - Amari C., Simon D., Bellon T., Plamont M.-A., Thiam A. R., Gueroui Z., **Controlling lipid droplet dynamics via tether condensates**, *Nature Chemical Biology*, 2025. https://www.nature.com/articles/s41589-025-01915-2 - Piroska L., Fenyi A., Thomas S., Plamont M.-A., Redeker V., Melki R., Gueroui Z., **α-synuclein liquid condensates fuel fibrillar α-synuclein growth**, *Science Advances*, 2023. https://www.science.org/doi/full/10.1126/sciadv.adg5663

Sustainable chemical synthesis design hinges on efficiency and deep mechanistic insight-two intimately linked principles. Our research focuses on the **development** **of advanced catalytic strategies**, encompassing transition metal catalysis, organocatalysis, photocatalysis and electrocatalysis. We design and implement versatile **multicomponent reactions** to access complex molecular architectures in a step- and atom-economical fashion. We perform **in-depth mechanistic investigations** using complementary experimental and analytical techniques, with a particular emphasis on elucidating the behavior of metal-catalyzed transformations. These studies guide the rational tuning of catalysts, conditions and reactor setups toward more robust and sustainable processes. Most recently, we have integrated **machine learning** tools to accelerate reaction optimization and guide catalyst and condition selection. This data-driven approach uncovers hidden reactivity patterns across our multicomponent and catalytic manifolds, thereby streamlining synthetic planning. Collectively, these efforts **expand the synthetic chemist's toolkit through rational design, enabling more efficient and sustainable routes to valuable molecular targets**.

The group uses molecular chemistry, chemical biology and biophysical chemistry to design responsive (supra)molecular tools to visualize and study biological processes with a strong emphasis on the development of fluorescent probes for bioimaging.  ### Chemogenetic probes and sensors to visualize cellular biochemistry Hybrid chemogenetic probes associating a genetically-encoded protein and a small molecular probe are a versatile approach for bioimaging that combine the selectivity of the genetic encoding with the flexibility of organic fluorophore design. Using the HaloTag technology, we have design a series of fluorogenic probes based on dipolar molecular rotors. These small molecules combine ease of synthesis, wavelength tunability, and strong fluorescence activation in presence of the HaloTag protein allowing wash-free imaging of subcellular organelles in live cells.^\[1-4\] We then adapted these fluorogenic scaffolds to yield genetically targeted sensors for subcellular calcium imaging and to follow protein exocytosis.^\[5-6\] Ongoing projects involve the development of Zn²⁺ and redox fluorescent sensors.^\[7\] We are also interested in the design of red-shifted bioluminescent reporters as an alternative to fluorescence imaging. **References:** \[1\] S. Bachollet, C. Addi, N. Pietrancosta, J.-M. M. Mallet, B. Dumat, _Chem. - A Eur. J._ **2020**, _26_, 14467-14473. \[2\] S. Bachollet, Y. Shpinov, F. Broch, H. Benaissa, A. Gautier, N. Pietrancosta, J.-M. Mallet, B. Dumat, _Org. Biomol. Chem._ **2022**, _20_, 3619-3628. \[3\] J. Coïs, S. Bachollet, L. Sanchez, N. Pietrancosta, V. Vialou, J. M. Mallet, B. Dumat, _Chem. - A Eur. J._ **2024**, _30_, e202400641. \[4\] B. Dumat, C. Chieffo, _Chem. - A Eur. J._ **2025**, _31_, e202404077. \[5\] S. Bachollet, N. Pietrancosta, J.-M. Mallet, B. Dumat, _Chem. Commun._ **2022**, _58_, 6594-6597. \[6\] J. Coïs, M.-L. Niepon, M. Wittwer, H. Sepasi Tehrani, P. Bun, J.-M. Mallet, V. Vialou, B. Dumat, _ACS Sensors_ **2024**, _9_, 4690-4700. \[7\] M. Čížková, L. Cattiaux, J. Pandard, M. Guille-Collignon, F. Lemaître, J. Delacotte, J.-M. Mallet, E. Labbé, O. Buriez, _Electrochem. commun._ **2018**, _97_, 46-50. ### Biomimetic functionalized lipid microparticles to study phagocytosis Phagocytosis is fundamental process of innate immunity by which phagocytic cells (_e.g._ macrophages) internalize objects larger than 0.5 microns. To study its mechanism, we have designed oil-in-water emulsion droplets of micrometric size funtionnalized with tailor-made fluorescent (glyco)lipids to target lectin receptors and report on the cellular adhesion^\[8\] or subsequent pH acidification during phagosome maturation.^\[9\] Ongoing projects are aimed at further investigating enzymatic activity and recycling during the late stages of phagocytosis. **References:** \[8\] S. Michelis, C. Pompili, F. Niedergang, J. Fattaccioli, B. Dumat, J.-M. Mallet, _ACS Appl. Mater. Interfaces_ **2024**, _16_, 9669-9679. \[9\] S. MichelisH ; Uhl, F. Niedergang, J. Fattaccioli, B. Dumat, J.-M. Mallet _BiorXiv_ **2026**, 11.20.685382 ### Functionalized Polysaccharides for biological applications Polysaccharides are natural polymers, an excellent alternative to synthetic polymers. Many are commercially available (in various sizes and functions) and, thanks to their hydrophilic properties, are particularly well-suited to biological applications. We have developed modified polysaccharides for coating particles: gold nanoparticles (in collaboration with F. Carn), Mil-100 iron nanoparticles (in collaboration with C. Serre and M. Lepoitevin), and for presenting multivalent antigens (in collaboration with Anna Maria Papini and Laurence Mulard). We are also preparing dextran-based micro- and nanoparticles for the development of a vaccine targeting Shigella flexneri (in collaboration with Laurence Mulard, Institut Pasteur). Cyclodextrins are cyclic oligosaccharides known to form host-guest complexes; we use them to prepare self-assembled nanogels (collaboration with K. Bouchemal). **References:** **Selective capture of anti-N-glucosylated NTHi adhesin peptide antibodies by a multivalent dextran conjugate**; Antonio Mazzoleni, Feliciana Real Fernandez, Francesca Nuti, Roberta Lanzillo, Vincenzo Brescia Morra, Paolo Dambruoso, Monica Bertoldo, Paolo Rovero, Jean-Maurice Mallet, Anna Maria Papini _Chembiochem_ **2022**, 23, 2022 e202100515 . doi :10.1002/cbic.202100515 **Flash Colloidal Assembly in Micro Flow System** Florent Voisin, Gerald Lelong, Jean-Michel Guigner, Thomas Bizien, Jean-Maurice Mallet, Florent Carn, _ACS Appl. Nano Mater._ **2022**, 5, 5, 6964-6971. doi. /10.1021/acsanm.2c00944 **Charge-Driven Arrested Phase-Separation of Polyelectrolyte-Gold Nanoparticle Assemblies Leading to Plasmonic Oligomers;** Florent Voisin, Gerald Lelong, Jean-Michel Guigner, Thomas Bizien, Jean-Maurice Mallet, Florent Carn, _Journal of Colloid and Interface Science, 630,_ **2023**_, 355-364_, doi 10.1016/j.jcis.2022.08.076 **Self-assembly of gold nanoparticles by chitosan for improved epinephrine detection using a portable surface enhanced Raman scattering device** Antoine Dowek, Florent Voisin, Laetitia Le, Céline Tan, Jean-Maurice Mallet, Florent Carn, Eric Caudron _Talanta_ **2023**, 251, 123752; _doi_ /j.talanta.2022.123752 **Cyclodextrin-based supramolecular nanogels decorated with mannose for short peptide encapsulation** Archana Sumohan Pillai, Mohamed Achraf Ben Njima, Yasmine Ayadi, Laurent Cattiaux, Ali Ladram, Christophe Piesse, Benoit Baptiste, Jean-François Gallard, Jean-Maurice Mallet, Kawthar Bouchemal _International Journal of Pharmaceutics_, 2024 DOI:10.1016/j.ijpharm.2024.124379 ### Chemical neurosciences The **Chemical Neurosciences** thematic develops an integrated chemical biology approach to decipher and modulate synaptic mechanisms at the molecular level. It combines **rational ligand design, molecular modeling and protein-protein interaction analysis** with advanced fluorescence imaging to target key synaptic proteins. Major achievements include the **first drug-like ligands of vesicular glutamate transporters (VGLUTs)**, enabling selective modulation of glutamatergic transmission from biochemistry to in vivo behavior. We also highlight that **flexible and dynamic protein-protein interfaces**, such as dopamine-NMDA receptor heteromers, can be **pharmacologically targeted**, overturning the concept of "undruggable" synaptic complexes. Together, these results provide **innovative molecular tools and therapeutic perspectives** for neurological and psychiatric disorders.