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<p>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 <i>B2m</i><sup>–/–</sup> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年1月3日

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  • Anirudh Sivakumar,
  • Hathaichanok Phuengkham,
  • Hitha Rajesh,
  • Quoc D. Mac,
  • Leonard C. Rogers,
  • Aaron D. Silva Trenkle,
  • Swapnil Subhash Bawage,
  • Robert Hincapie,
  • Zhonghan Li,
  • Sofia Vainikos,
  • Inho Lee,
  • Min Xue,
  • Peng Qiu,
  • M. G. Finn,
  • Gabriel A. Kwong

摘要

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.