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Tina Briolay,1 Judith Fresquet,1 Damien Meyer,2 Brigitte Kerfelec,2 Patrick Chames,2 Eléna Ishow,3 Christophe Blanquart1 1Nantes Université, INSERM UMR 1307, CNRS UMR 6075, Université d’Angers, CRCI2NA, Nantes, F-44000, France; 2Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France; 3Nantes Université, CNRS, CEISAM, UMR 6230, Nantes, F-44000, FranceCorrespondence: Christophe Blanquart, CRCI2NA, INSERM UMR 1307/CNRS UMR 6075, IRS-UN, 8 Quai Moncousu, BP70721, Cedex 1, Nantes, 44007, France, Tel +33 228 080 238, Email christophe.blanquart@inserm.frIntroduction: Most current anti-cancer therapies are associated with major side effects due to a lack of tumor specificity. Appropriate vectorization of drugs using engineered nanovectors is known to increase local concentration of therapeutic molecules in tumors while minimizing their side effects. Mesothelin (MSLN) is a well-known tumor associated antigen overexpressed in many malignancies, in particular in malignant pleural mesothelioma (MPM), and various MSLN-targeting anticancer therapies are currently evaluated in preclinical and clinical assays. In this study, we described, for the first time, the functionalization of fluorescent organic nanoassemblies (NA) with a nanobody (Nb) targeting MSLN for the specific targeting of MSLN expressing MPM cancer cells.Methods: Cell lines from different cancer origin expressing or not MSLN were used. An Nb directed against MSLN was coupled to fluorescent NA using click chemistry. A panel of endocytosis inhibitors was used to study targeted NA internalization by cells. Cancer cells were grown in 2D or 3D and under a flow to evaluate the specificity of the targeted NA. Binding and internalization of the targeted NA were studied using flow cytometry, confocal microscopy and transmission electron microscopy.Results: We show that the targeted NA specifically bind to MSLN-expressing tumor cells. Moreover, such functionalized NA appear to be internalized