Thèse Bioingénierie de Surface pour la Conception de Bandelettes Immunochromatographiques Fiables et Ultra-Sensibles à Base de Nanoparticules Luminescentes H/F

Institut Polytechnique de Paris École polytechnique

Établissement : Institut Polytechnique de Paris École polytechnique
École doctorale : Ecole Doctorale de l'Institut Polytechnique de Paris
Laboratoire de recherche : PMC - Laboratoire de Physique de la Matière Condensée
Direction de la thèse : Anne Chantal GOUGET - LAEMMEL ORCID 0000000274779200
Début de la thèse : 2026-10-01
Date limite de candidature : 2026-04-26T23:59:59

L'adsorption non spécifique de protéines ou de micro-organismes peut fortement compromettre la fiabilité et la sensibilité des tests diagnostiques, en particulier ceux reposant sur des biocapteurs tels que les tests ELISA ou encore LFA (essais en flux latéral). Lorsqu'ils sont exposés à des milieux biologiques complexes tels que le sang, la salive ou des échantillons environnementaux, ces dispositifs sont soumis à l'adsorption non sélective de biomolécules et de micro-organismes sur la surface du capteur. Ce phénomène peut masquer les éléments de reconnaissance (anticorps, aptamères, oligonucléotides) et générer des faux positifs ou un bruit de fond élevé, réduisant ainsi la sensibilité, la sélectivité et la reproductibilité des analyses. Dans ce contexte, la maîtrise de l'adhésion non spécifique par la bioingénierie de surface - communément désignée sous le terme d'« antifouling » - constitue un enjeu scientifique majeur et un prérequis indispensable au transfert technologique de ces dispositifs vers des applications cliniques, environnementales et industrielles.
Le présent projet se concentrera sur le développement de LFA utilisant des nanoparticules luminescentes dopées aux terres rares, reconnues pour permettre une détection rapide, sensible et à faible coût. L'objectif est double :
1.améliorer la sensibilité de détection en développant de nouvelles stratégies de fonctionnalisation capables de limiter l'adsorption non spécifique ;
2.optimiser la taille et le rendement quantique des nanoparticules afin de permettre la détection directe de traces d'ADN ou d'ARN viral, sans recours à des enzymes ni à des étapes d'amplification.
Cette thèse se fera en étroite collaboration avec Antigoni Alexandrou du LOB à l'Ecole Polytechnique.

Non-specific protein and microbial interactions can strongly compromise the accuracy and reliability of diagnostic tests, especially those based on biosensors or surface-dependent detection (enzyme-linked immunosorbent assays - ELISA, lateral flow assays - LFA, or electrochemical tests). When such tests are exposed to complex biological media (blood, saliva, environmental samples), biomolecules and microorganisms can adsorb non-selectively onto the sensor surface by masking recognition elements (antibodies, aptamers, receptors) and generating false positive signals or high background noise. This reduces sensor sensitivity, selectivity, and reproducibility. Therefore, controlling non-specific adhesion through surface chemistry engineering has become a central challenge in biosensor research and a prerequisite for their translation from laboratory settings to clinical, environmental, and industrial applications.
Among the various diagnostic tests, LFA are particularly attractive because they enable rapid, inexpensive, and easy-to-use detection at the point of care and in low-resource settings. They are paper-based platforms that detect a target analyte (antigen, antibody, or nucleic acid) through capillary-driven flow across a functionalized strip [1]. They are composed of a sample pad (where the sample is deposited), a conjugate release pad containing typically detection-antibody functionalized gold nanoparticles which will reveal the target, and two lines, a test and control line with immobilized capture antibodies specific towards the target and the functionalized nanoparticles, respectively.
Although the fundamental principle of lateral flow assays has remained largely unchanged for decades, continuous improvements in materials, surface chemistry, and detection strategies are continuously implemented in order to improve their sensitivity, reproducibility, and enable the simultaneous detection of multiple analytes. In particular, LFA tests with sensitivity approaching that of laboratory ELISA tests are highly desirable.
Recently, the Laboratoire de Physique de la Matière Condensée in collaboration with the Laboratoire d'Optique et Biosciences has developed lanthanide-based nanoparticles (YVO4:Eu) as new, bright luminescent labels to improve the sensitivity of LFA detection, in replacement of absorbing gold nanoparticles. [2,3] The remarkable optical and chemical properties of these particles (high UV absorbance, large Stokes shift, photostability, colloidal stability in aqueous buffers, and easy functionalization) qualifies them for the detection of biomolecules at high sensitivities in the femtomolar range for protein detection [4] to attomolar range for nucleic acid detection in ELISA format without the need for enzymes or amplification [5] and in the picomolar range for protein detection in the LFA format.[3,4] Te next step is to implement high-sensitivity nucleic acid detection in LFA format, in particular for the detection of viral DNA or RNA in low-resource settings. To be able to implement competitive viral detection in LFA format, a significant increase of the LFA test sensitivity is necessary.

The objective of this PhD thesis is i) first to improve the LFA detection sensitivity and accuracy, notably through the development of innovative functionalization strategies capable of limiting non-specific adsorption, and secondly ii) to optimize the size, shape, and quantum yield of these nanoparticles for detection of short nucleic acid fragment traces in LFA format.

More precisely, several axes will be first studied at the PMC lab:
i)The optimization of the LFA membrane chemistry by functionalizing the nitrocellulose membrane with antifouling hydrophilic polymers (type zwitterion, PEG, polyglycerol) terminated with adequate functional groups (type carboxy or azido)
ii)The covalent attachment of capture oligonucleotides within the control and test lines (either by amidation via EDC/NHS or via click chemistry) ; the effect of their grafting density on the antifouling capabilities will be investigated by working on silicon model surfaces for quantitative analysis [6]
iii)The synthesis of YVO4:Eu nanoparticles with enhanced optical properties6 and their subsequent stabilization with antifouling functionalized polymers [7]
iv)The proof-of-concept by realizing an LFA test for detection of nucleic acids first in aqueous buffer and then in complex biological and environmental samples (serum, blood, and other body fluids, waste water, ...) using antifouling nanoparticles and antifouling nitrocellulose membrane.
Then, concerning the second objective of this PhD project, the size, shape, and quantum yield of YVO4:Eu nanoparticles will be optimized for the LFA detection format, based on recently developed synthesis strategies allowing a control of these parameters.[6] Larger nanoparticle size and higher quantum yield lead to a higher emission signal and should enable enhanced sensitivity. In the case of the LFA format, however, the porosity of the nitrocellulose membrane should also be taken into account and shall influence the optimal nanoparticle size. At LOB, we will determine the optimal size and shape of these new nanoparticles for the development of LFA tests for the fast and sensitive detection of viral DNA/RNA traces without the need of enzymes nor amplification. The performance in terms of sensitivity and reproducibility will be evaluated in different physiological matrices.