Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Nanosensors for real-time intracellular analytics

Nature Nanotechnology (2025)Cite this article

Subjects

Abstract

A fundamental goal in modern biology and precision medicine is to acquire rich, multi-omics-style information from cells, including transcriptomic, proteomic, metabolic and electrophysiological data, in real time and at single-cell resolution. However, current techniques often rely on destructive endpoint assays that require cell lysis, losing spatial, temporal and dynamic context. Nanoscale sensors offer a transformative solution by enabling minimally invasive, continuous monitoring of intracellular activities. Here we propose a spatial classification of intracellular sensing technologies—near cell, on cell and in cell—and use this framework to evaluate the sensing modalities on the basis of their invasiveness, signal fidelity and resolution. We highlight emerging sensor platforms that are capable of detecting ions, metabolites, electrical signals and mechanical changes, as well as artificial intelligence-driven strategies for decoding complex cellular data streams. We further consider the integration of these nanosensors into three-dimensional, physiologically relevant models such as organoids to create ‘smart organoids’ that report on their internal state autonomously and in real time. Finally, we discuss the major challenges in achieving intelligent intracellular sensing, including issues of sensor miniaturization, biocompatibility, multiplexing and three-dimensional integration. Together, these advances set the stage for a new era of dynamic, high-resolution cell profiling that can accelerate drug discovery, disease modelling and personalized medicine.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Real-time in situ biomolecular intracellular monitoring.
Fig. 2: Near-cell sensors.
Fig. 3: On-cell techniques for the monitoring of cellular biomarkers.
Fig. 4: On-cell optical techniques for the monitoring of cellular biomarkers.
Fig. 5: In-cell technique of cellular biomarker monitoring.

Similar content being viewed by others

References

  1. Liu, Z. & Zhang, Z. Mapping cell types across human tissues. Science 376, 695–696 (2022).

    Article  CAS  PubMed  Google Scholar 

  2. Yamanaka, S. Pluripotent stem cell-based cell therapy—promise and challenges. Cell Stem Cell 27, 523–531 (2020).

    Article  CAS  PubMed  Google Scholar 

  3. Baysoy, A., Bai, Z., Satija, R. & Fan, R. The technological landscape and applications of single-cell multi-omics. Nat. Rev. Mol. Cell Biol. 24, 695–713 (2023).

    Article  CAS  PubMed  Google Scholar 

  4. Qiu, S. et al. Small molecule metabolites: discovery of biomarkers and therapeutic targets. Signal Transduct. Target. Ther. 8, 132 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Rad, M. S., Cohen, L. B., Braubach, O. & Baker, B. J. Monitoring voltage fluctuations of intracellular membranes. Sci. Rep. 8, 6911 (2018).

    Article  Google Scholar 

  6. Zhou, C., Zhao, W.-x., You, F.-t., Geng, Z.-x. & Peng, H.-s. Highly stable and luminescent oxygen nanosensor based on ruthenium-containing metallopolymer for real-time imaging of intracellular oxygenation. ACS Sens. 4, 984–991 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. He, C., Lu, K. & Lin, W. Nanoscale metal–organic frameworks for real-time intracellular pH sensing in live cells. J. Am. Chem. Soc. 136, 12253–12256 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang, X., Ogorevc, B. & Wang, J. Solid-state pH nanoelectrode based on polyaniline thin film electrodeposited onto ion-beam etched carbon fiber. Anal. Chim. Acta 452, 1–10 (2002).

    Article  CAS  Google Scholar 

  9. Soldà, A. et al. Glucose and lactate miniaturized biosensors for SECM-based high-spatial resolution analysis: a comparative study. ACS Sens. 2, 1310–1318 (2017). This study develops miniaturized enzymatic glucose and lactate biosensors using Pt ultramicroelectrodes and enzyme immobilization to enhance the sensitivity and spatial resolution for monitoring metabolic activity at the single-cell level with SECM.

    Article  PubMed  Google Scholar 

  10. Yuan, X. et al. Versatile live-cell activity analysis platform for characterization of neuronal dynamics at single-cell and network level. Nat. Commun. 11, 4854 (2020). This study presents a dual-mode high-density microelectrode array platform that enables long-term, label-free electrophysiological imaging of neuronal cultures at subcellular, single-cell, and network levels, integrating full-frame (19,584 electrodes) and high-SNR (246 channels) recording modes to support high-throughput analysis of neuronal dynamics.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jung, H. S. et al. CMOS electrochemical pH localizer-imager. Sci. Adv. 8, eabm6815 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Cools, J. et al. 3D microstructured carbon nanotube electrodes for trapping and recording electrogenic cells. Adv. Funct. Mater. 27, 1701083 (2017).

    Article  Google Scholar 

  13. Zhou, X.-L., Yang, Y., Wang, S. & Liu, X.-W. Surface plasmon resonance microscopy: from single-molecule sensing to single-cell imaging. Angew. Chem. 132, 1792–1801 (2020).

    Article  Google Scholar 

  14. Tanaka, H. et al. Potassium ion dynamics imaging through supported lipid bilayers with surface plasmon resonance microscopy. ACS Photonics 9, 3412–3420 (2022).

    Article  CAS  Google Scholar 

  15. Shinohara, H., Sakai, Y. & Mir, T. A. Real-time monitoring of intracellular signal transduction in PC12 cells by two-dimensional surface plasmon resonance imager. Anal. Biochem. 441, 185–189 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Nascimento, R. A. S. et al. Single cell “glucose nanosensor” verifies elevated glucose levels in individual cancer cells. Nano Lett. 16, 1194–1200 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li, X., Dunevall, J. & Ewing, A. G. Quantitative chemical measurements of vesicular transmitters with electrochemical cytometry. Acc. Chem. Res. 49, 2347–2354 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Hu, K., Vo, K. L. L., Hatamie, A. & Ewing, A. G. Quantifying intracellular single vesicular catecholamine concentration with open carbon nanopipettes to unveil the effect of L-DOPA on vesicular structure. Angew. Chem. 134, e202113406 (2022).

    Article  Google Scholar 

  19. Xie, C., Lin, Z., Hanson, L., Cui, Y. & Cui, B. Intracellular recording of action potentials by nanopillar electroporation. Nat. Nanotechnol. 7, 185–190 (2012). This study demonstrates the use of vertically aligned nanopillar electrodes to achieve long-term, high-fidelity intracellular and extracellular recordings of cardiomyocyte action potentials by forming tight membrane–electrode junctions and enabling reversible, localized electroporation to significantly reduce cell–electrode impedance, enabling the sensitive pharmacological analysis of ion channel activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jahed, Z. et al. Nanocrown electrodes for parallel and robust intracellular recording of cardiomyocytes. Nat. Commun. 13, 2253 (2022). This study develops semi-hollow nanocrown electrodes for intracellular action potential recordings, enablingparallel and long-term recording in a minimally invasive manner.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Abbott, J. et al. A nanoelectrode array for obtaining intracellular recordings from thousands of connected neurons. Nat. Biomed. Eng. 4, 232–241 (2019). This study presents a CMOS-based, massively parallel intracellular recording system integrating 4,096 vertical nanoelectrode sites, enabling the high-resolution measurement of chemical synapse characteristics and large-scale mapping of synaptic connectivity across neuronal networks.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu, R. et al. Ultra-sharp nanowire arrays natively permeate, record, and stimulate intracellular activity in neuronal and cardiac networks. Adv. Funct. Mater. 32, 2108378 (2022).

    Article  CAS  PubMed  Google Scholar 

  23. Spira, M. E., Shmoel, N., Huang, S.-H. M. & Erez, H. Multisite attenuated intracellular recordings by extracellular multielectrode arrays, a perspective. Front. Neurosci. 12, 212 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Desbiolles, B. X. E., de Coulon, E., Bertsch, A., Rohr, S. & Renaud, P. Intracellular recording of cardiomyocyte action potentials with nanopatterned volcano-shaped microelectrode arrays. Nano Lett. 19, 6173–6181 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Abbott, J. et al. CMOS nanoelectrode array for all-electrical intracellular electrophysiological imaging. Nat. Nanotechnol. 12, 460–466 (2017). This study introduces a scalable 3D field-effect transistor array platform for the accurate, minimally invasive recording of transmembrane potentials, enabling high-resolution measurements of intracellular signal conduction in cardiomyocytes and cardiac tissue constructs.

    Article  CAS  PubMed  Google Scholar 

  26. Gu, Y. et al. Three-dimensional transistor arrays for intra- and inter-cellular recording. Nat. Nanotechnol. 17, 292–300 (2022).

    Article  CAS  PubMed  Google Scholar 

  27. Hanif, S. et al. Organic cyanide decorated SERS active nanopipettes for quantitative detection of hemeproteins and Fe3+ in single cells. Anal. Chem. 89, 2522–2530 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Lussier, F. et al. Dynamic-SERS optophysiology: a nanosensor for monitoring cell secretion events. Nano Lett. 16, 3866–3871 (2016).

    Article  CAS  PubMed  Google Scholar 

  29. Yan, R. et al. Nanowire-based single-cell endoscopy. Nat. Nanotechnol. 7, 191–196 (2012).

    Article  CAS  Google Scholar 

  30. Rotenberg, M. Y. et al. Silicon nanowires for intracellular optical interrogation with subcellular resolution. Nano Lett. 20, 1226–1232 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shibata, T. et al. Photocatalytic nanofabrication and intracellular Raman imaging of living cells with functionalized AFM probes. Micromachines 11, 495 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ichikawa, T. et al. Protocol for live imaging of intracellular nanoscale structures using atomic force microscopy with nanoneedle probes. STAR Protoc. 4, 102468 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Penedo, M. et al. Visualizing intracellular nanostructures of living cells by nanoendoscopy-AFM. Sci. Adv. 7, eabj4990 (2023).

    Article  Google Scholar 

  34. Ding, H., Su, B. & Jiang, D. Recent advances in single cell analysis by electrochemiluminescence. ChemistryOpen 12, e202200113 (2023).

    Article  CAS  PubMed  Google Scholar 

  35. Zhang, H. et al. Electrochemiluminescence-microscopy for microRNA imaging in single cancer cell combined with chemotherapy-photothermal therapy. Anal. Chem. 91, 12581–12586 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Zhou, X. et al. A new highly selective fluorescent K+ sensor. J. Am. Chem. Soc. 133, 18530–18533 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Iamshanova, O., Mariot, P., Lehen’kyi, V. & Prevarskaya, N. Comparison of fluorescence probes for intracellular sodium imaging in prostate cancer cell lines. Eur. Biophys. J. 45, 765–777 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Grienberger, C. & Konnerth, A. Imaging calcium in neurons. Neuron 73, 862–885 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Li, P. et al. A near-infrared-emitting fluorescent probe for monitoring mitochondrial pH. Chem. Commun. 50, 7184–7187 (2014).

    Article  CAS  Google Scholar 

  40. Mita, M. et al. Green fluorescent protein-based glucose indicators report glucose dynamics in living cells. Anal. Chem. 91, 4821–4830 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Tang, J. et al. Noninvasive and highly selective monitoring of intracellular glucose via a two-step recognition-based nanokit. Anal. Chem. 89, 8319–8327 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Li, L. et al. Simultaneous quantitation of Na+ and K+ in single normal and cancer cells using a new near-infrared fluorescent probe. Anal. Chem. 87, 6057–6063 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Choe, M. & Titov, D. V. Genetically encoded tools for measuring and manipulating metabolism. Nat. Chem. Biol. 18, 451–460 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wu, J. et al. Motion-based DNA detection using catalytic nanomotors. Nat. Commun. 1, 36 (2010).

    Article  PubMed  Google Scholar 

  45. Yu, X., Li, Y., Wu, J. & Ju, H. Motor-based autonomous microsensor for motion and counting immunoassay of cancer biomarker. Anal. Chem. 86, 4501–4507 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Balasubramanian, S. et al. Micromachine-enabled capture and isolation of cancer cells in complex media. Angew. Chem. Int. Ed. 50, 4161–4164 (2011).

    Article  CAS  Google Scholar 

  47. Esteban-Fernández de Ávila, B. et al. Single cell real-time miRNAs sensing based on nanomotors. ACS Nano 9, 6756–6764 (2015).

    Article  PubMed  Google Scholar 

  48. Pal, M. et al. Helical nanobots as mechanical probes of intra- and extracellular environments. J. Phys. Condens. Matter 32, 224001 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Hurt, R. C. et al. Genomically mined acoustic reporter genes for real-time in vivo monitoring of tumors and tumor-homing bacteria. Nat. Biotechnol. 41, 919–931 (2023). This study develops improved acoustic reporter genes that offer enhanced ultrasound contrast and stable in vivo expression for the non-invasive imaging of tumour colonization and gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Joy, B., Cai, Y., Bono, D. C. & Sarkar, D. Cell Rover—a miniaturized magnetostrictive antenna for wireless operation inside living cells. Nat. Commun. 13, 5210 (2022). This study introduces the Cell Rover, a magnetic antenna that is capable of wirelessly operating inside living cells, providing a platform for advanced intracellular sensing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gómez-Martínez, R. et al. Silicon chips detect intracellular pressure changes in living cells. Nat. Nanotechnol. 8, 517–521 (2013). This study presents a silicon chip internalized into living cells, enabling the direct measurement of intracellular pressure changes in a minimally invasive manner.

    Article  PubMed  Google Scholar 

  52. Airaghi Leccardi, M. J. I. et al. Light-induced rolling of azobenzene polymer thin films for wrapping subcellular neuronal structures. Commun. Chem. 7, 249 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rahmani, K. et al. Intelligent in-cell electrophysiology: reconstructing intracellular action potentials using a physics-informed deep learning model trained on nanoelectrode array recordings. Nat. Commun. 16, 657 (2025). This study develops a physics-informed deep learning model to reconstruct intracellular action potentials from extracellular recordings on nanoelectrode and microelectrode arrays, enabling high-throughput, non-invasive electrophysiology for cardiotoxicity assessments without direct internalization of the probe for sensing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Krumm, A. & Carey, C. Real-time monitoring of cellular metabolic activity: intracellular oxygen. Nat. Methods 13, i–ii (2016).

    Article  Google Scholar 

  55. Hu, Q. et al. Genetically encoded biosensors for evaluating NAD+/NADH ratio in cytosolic and mitochondrial compartments. Cell Rep. Methods 1, 100116 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Giorgio, M., Trinei, M., Migliaccio, E. & Pelicci, P. G. Hydrogen peroxide: A metabolic by-product or a common mediator of ageing signals?. Nat. Rev. Mol. Cell Biol. 9, 722–728 (2007).

    Article  Google Scholar 

  57. Shu, Y. et al. Isolated cobalt atoms on N-doped carbon as nanozymes for hydrogen peroxide and dopamine detection. ACS Appl. Nano Mater. 4, 7954–7962 (2021).

    Article  CAS  Google Scholar 

  58. Jaworska, A., Malek, K. & Kudelski, A. Intracellular pH – advantages and pitfalls of surface-enhanced Raman scattering and fluorescence microscopy – a review. Spectrochim. Acta A Mol. Biomol. Spectrosc. 251, 119410 (2021).

    Article  CAS  PubMed  Google Scholar 

  59. Yu, X.-M., Groveman, B. R., Fang, X.-Q. & Lin, S.-X. The role of intracellular sodium (Na+) in the regulation of calcium (Ca2+)-mediated signaling and toxicity. Health (Irvine Calif.). 2, 8–15 (2010).

    PubMed  PubMed Central  Google Scholar 

  60. Shi, X.-M. et al. A supersmall single-cell nanosensor for intracellular K+ detection. CCS Chem. 3, 2359–2367 (2021).

    Article  CAS  Google Scholar 

  61. Bootman, M. D. & Bultynck, G. Fundamentals of cellular calcium signaling: a primer. Cold Spring Harb. Perspect. Biol. 12, a038802 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shindo, Y., Yamanaka, R., Suzuki, K., Hotta, K. & Oka, K. Intracellular magnesium level determines cell viability in the MPP+ model of Parkinson’s disease. Biochim. Biophys. Acta Mol. Cell Res. 1853, 3182–3191 (2015).

    Article  CAS  Google Scholar 

  63. Stauber, T. & Jentsch, T. J. Chloride in vesicular trafficking and function. Annu. Rev. Physiol. 75, 453–477 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Bergwitz, C. & Jüppner, H. Phosphate sensing. Adv. Chronic Kidney Dis. 18, 132–144 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was in part supported by the Air Force Office of Scientific Research YIP award (AFOSR FA9550-23-1-0090) and UC San Diego Materials Research Science and Engineering Center (UC San Diego MRSEC), supported by the National Science Foundation (Grant DMR-2011924) to Z.J. In addition, A.C. is grateful for the support of the ‘Margarita Salas’ postdoctoral fellowship from the European Union Next Generation, EU.

Author information

Author notes

  1. These authors contributed equally: Einollah Sarikhani, Kuldeep Mahato.

Authors and Affiliations

  1. Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California San Diego, La Jolla, CA, USA

    Einollah Sarikhani, Kuldeep Mahato, Ana Casanova, Keivan Rahmani, Joseph Wang & Zeinab Jahed

  2. Shu Chein-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, USA

    Zeinab Jahed

Authors
  1. Einollah Sarikhani
    View author publications

    Search author on:PubMed Google Scholar

  2. Kuldeep Mahato
    View author publications

    Search author on:PubMed Google Scholar

  3. Ana Casanova
    View author publications

    Search author on:PubMed Google Scholar

  4. Keivan Rahmani
    View author publications

    Search author on:PubMed Google Scholar

  5. Joseph Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Zeinab Jahed
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Joseph Wang or Zeinab Jahed.

Ethics declarations

Competing interests

The authors declare no competing interests

Peer review

Peer review information

Nature Nanotechnology thanks Jayoung Kim and Bing Li for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sarikhani, E., Mahato, K., Casanova, A. et al. Nanosensors for real-time intracellular analytics. Nat. Nanotechnol. (2025). https://doi.org/10.1038/s41565-025-02032-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41565-025-02032-w

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing