Graphene-Based Opto-Electronic Platform for Ultra-Sensitive Biomarker Detection at Zeptomolar Concentrations

Matteo Piscitelli; Cinzia Di Franco; Giuseppe Valerio Bianco; Giovanni Bruno; Eleonora Macchia; Luisa Torsi; Gaetano Scamarcio

doi:10.1002/smtd.202402026

Graphene-Based Opto-Electronic Platform for Ultra-Sensitive Biomarker Detection at Zeptomolar Concentrations

Matteo Piscitelli, Cinzia Di Franco^*, Giuseppe Valerio Bianco, Giovanni Bruno, Eleonora Macchia, Luisa Torsi, Gaetano Scamarcio^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

Abstract

A ground-breaking graphene-based biosensor designed for label-free detection of immunoglobulin M (IgM) achieving a remarkable concentration of 100 zeptomolar (10−19 m), is reported. The sensor is a two-terminal device and incorporates a millimeter-wide gold interface, bio-functionalized with ≈1012 anti-IgM antibodies and capacitively coupled to a bare graphene electrode through a water-soaked paper strip. In this configuration, few affinity binding events trigger a collective electrostatic reorganization of the protein layer, leading to an extended surface potential (SP) shift of the biofunctionalized Au surface. The SP shift, mediated by electrolyte capacitive coupling, induces a corresponding shift in the Fermi level of graphene. This shifts the graphene phonon frequencies, which are measured by Raman spectroscopy. Decoupling the sensing interface from the transducing graphene layer provides flexibility in surface chemistry modifications, while preserving the graphene integrity. A key aspect of this biosensor is its ability to precisely determine the graphene charge neutrality point from the voltage dependence of phonon frequency shifts, enabling detections of biomarker at unprecedented low concentrations. The integration of graphene with optical probing demonstrates a proof-of-concept and establishes a ground-breaking approach to in situ biomarker detection, setting the stage for a future generation of portable opto-electronic high-performance diagnostic tools for single-marker detection.

Original language	English
Article number	2402026
Number of pages	10
Journal	Small Methods
Volume	9
Issue number	8
DOIs	https://doi.org/10.1002/smtd.202402026
Publication status	Published - 20 Aug 2025
Externally published	Yes
MoE publication type	A1 Journal article-refereed

Funding

PNRR MUR project PE0000023-NQSTI – National Quantum Science and Technolgy Institute; MUR – Dipartimenti di Eccellenza 2023–2027 – Quantum Sensing and Modelling for One-Health (QuaSiModO); Centro di Innovazione Regionale Digital Assay, Regione PUGLIA Delibera Regionale n 702 del 08/11/2022 CUP B93C22000840001; NoOne-A binary sensor with single-molecule digit to discriminate biofluids enclosing zero or at least one biomarker, ERC Stg2021, GA:101040383; PRIN project prot.2017RHX2E4 “At the forefront of Analytical ChemisTry: disrUptive detection technoLogies to improve; Italian network of excellence for advanced diagnosis (INNOVA), Ministero della Salute -code PNC-E3-2022-23683266 PNC-HLS-DA, CUP: C43C22001630001; Complementary National Plan PNC-I.1 ″Research initiatives for innovative technologies and pathways in the health and welfare sector” D.D. 931 of 06/06/2022, DARE – DigitAl lifelong pRevEntion initiative, code PNC0000002, CUP: B53C22006420001; Tecnologie portatili e protocolli innovativi per la diagnosi ultrasensibile di Xylella fastidiosa direttamente in piante e vettori (1LIVEXYLELLA) Ministero dell'agricoltura, della sovranità alimentare e delle foreste – MIPAAF D.M. n.419161 del 13/09/2022; Research actions for reducing the impact on agricultural and natural ecosystems of the harmful plant pathogen Xylella fastidiosa (REACH-XY) – CUP B93C22001920001. [Correction added on January 24, 2025, after first online publication: Supporting information replaced.] Open access publishing facilitated by Consiglio Nazionale delle Ricerche, as part of the Wiley - CRUI-CARE agreement.

Keywords

Raman spectroscopy
Biosensors
Graphene
Single-molecule

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abstract = "A ground-breaking graphene-based biosensor designed for label-free detection of immunoglobulin M (IgM) achieving a remarkable concentration of 100 zeptomolar (10−19 m), is reported. The sensor is a two-terminal device and incorporates a millimeter-wide gold interface, bio-functionalized with ≈1012 anti-IgM antibodies and capacitively coupled to a bare graphene electrode through a water-soaked paper strip. In this configuration, few affinity binding events trigger a collective electrostatic reorganization of the protein layer, leading to an extended surface potential (SP) shift of the biofunctionalized Au surface. The SP shift, mediated by electrolyte capacitive coupling, induces a corresponding shift in the Fermi level of graphene. This shifts the graphene phonon frequencies, which are measured by Raman spectroscopy. Decoupling the sensing interface from the transducing graphene layer provides flexibility in surface chemistry modifications, while preserving the graphene integrity. A key aspect of this biosensor is its ability to precisely determine the graphene charge neutrality point from the voltage dependence of phonon frequency shifts, enabling detections of biomarker at unprecedented low concentrations. The integration of graphene with optical probing demonstrates a proof-of-concept and establishes a ground-breaking approach to in situ biomarker detection, setting the stage for a future generation of portable opto-electronic high-performance diagnostic tools for single-marker detection.",

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Graphene-Based Opto-Electronic Platform for Ultra-Sensitive Biomarker Detection at Zeptomolar Concentrations

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