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AND-gated protease-activated nanosensors for programmable detection of anti-tumour immunity

Nature Nanotechnology volume 20, pages 441–450 (2025)Cite this article

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Abstract

The forward design of biosensors that implement Boolean logic to improve detection precision primarily relies on programming genetic components to control transcriptional responses. However, cell- and gene-free nanomaterials programmed with logical functions may present lower barriers for clinical translation. Here we report the design of activity-based nanosensors that implement AND-gate logic without genetic parts via bi-labile cyclic peptides. These actuate by releasing a reporter if and only if cleaved by a specific pair of proteases. AND-gated nanosensors that detect the concomitant activity of the granzyme B protease secreted by CD8 T cells and matrix metalloproteinases overexpressed by cancer cells identify the unique condition of cytotoxic T cell killing of tumour cells. In preclinical mouse models, AND-gated nanosensors discriminate tumours that are responsive to immune checkpoint blockade therapy from B2m–/– tumours that are resistant to it, minimize signals from tissues without co-localized protease expression including the lungs during acute influenza infection, and release a reporter locally in tissue or distally in the urine for facile detection.

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Fig. 1: Asymmetric bi-labile cyclic peptide nanosensors implement AND-gate logic.
Fig. 2: Multivalent presentation of AND-gated peptides improves proteolysis kinetics.
Fig. 3: AND-gated nanosensors selectively report on T cell killing of cancer cells.
Fig. 4: AND-gated nanosensors detect anti-tumour responses during ICBT.
Fig. 5: AND-gated nanosensors increase specificity by requiring co-localized proteases for activation.
Fig. 6: AND-gated nanosensors increase selectivity of on-tumour detection.

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Data availability

The source data underlying the main text figures (Figs. 1–6) and Supplementary figures are provided as source data files. All raw data and calculations used to generate plotted data are provided with this paper in the source data files. Image source data for Supplementary figures are provided at the end of the Supplementary Information file. Source data are provided with this paper.

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Acknowledgements

This work was funded in part by National Institutes of Health (NIH) grants 5U01CA265711 (G.A.K., P.Q. and M.G.F.), 5R01CA237210 (G.A.K.), 1DP2HD091793 (G.A.K.) and 5DP1CA280832 (G.A.K.). The authors were supported by the National Science Foundation (NSF) Graduate Research Fellowships Program (grant DGE-2039655, A.S. and A.D.S.T.) and the National Institutes of Health Cell and Tissue Engineering Training Program T32GM145735 (A.D.S.T.). This work was performed in part at the Georgia Tech Institute for Electronics and Nanotechnology, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (grant ECCS-1542174). This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the staff at Georgia Tech’s Systems Mass Spectrometry Core, Cellular Analysis and Cytometry Core, Organic Materials Characterization Laboratory and Department of Animal Resources for their assistance in performing our studies.

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Authors and Affiliations

  1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA

    Anirudh Sivakumar, Hathaichanok Phuengkham, Hitha Rajesh, Quoc D. Mac, Leonard C. Rogers, Aaron D. Silva Trenkle, Swapnil Subhash Bawage, Sofia Vainikos, Inho Lee, Peng Qiu & Gabriel A. Kwong

  2. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA

    Robert Hincapie & M. G. Finn

  3. Department of Chemistry, University of California Riverside, Riverside, CA, USA

    Zhonghan Li & Min Xue

  4. Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA

    Gabriel A. Kwong

  5. Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA, USA

    Gabriel A. Kwong

  6. Integrated Cancer Research Center, Georgia Institute of Technology, Atlanta, GA, USA

    Gabriel A. Kwong

  7. The Georgia Immunoengineering Consortium, Emory University and Georgia Institute of Technology, Atlanta, GA, USA

    Gabriel A. Kwong

  8. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Gabriel A. Kwong

Authors
  1. Anirudh Sivakumar
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  2. Hathaichanok Phuengkham
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Contributions

A.S. and G.A.K. conceived the idea. A.S., H.P., Q.D.M., M.X., P.Q., M.G.F. and G.A.K. designed the experiments and interpreted the results. A.S., H.P., H.R., L.C.R., A.D.S.T., S.S.B., R.H., Z.L., S.V. and I.L. synthesized the materials and carried out the experiments. A.S. and G.A.K. wrote the paper.

Corresponding author

Correspondence to Gabriel A. Kwong.

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Competing interests

G.A.K. is an equity shareholder of, and consults for, Sunbird Bio and Port Therapeutics. This study could affect his personal financial status. The terms of this arrangement have been reviewed and approved by Georgia Tech in accordance with its conflict-of-interest policies. A.S., Q.D.M. and G.A.K. are listed as inventors on patent application (PCT/US2020/030132) pertaining to the results of the paper. The patent applicant is the Georgia Tech Research Corporation. The patent is published (WO2020191416A3). The remaining authors declare no competing interests.

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Sivakumar, A., Phuengkham, H., Rajesh, H. et al. AND-gated protease-activated nanosensors for programmable detection of anti-tumour immunity. Nat. Nanotechnol. 20, 441–450 (2025). https://doi.org/10.1038/s41565-024-01834-8

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