# Redox‐Programmed Activation of a Dual‐Modal Probe for High‐Fidelity Tumor Delineation and Image‐Guided Surgery

## TL;DR

A new dual-modality probe called GAP9 is developed to accurately detect tumors and guide surgery by activating only in cancerous tissue, reducing false signals and improving detection of small lesions.

## Contribution

The paper introduces a redox-programmed strategy to create a dual-modal probe that activates specifically in tumors based on glutathione levels.

## Key findings

- GAP9 remains inactive in normal tissues, minimizing false signals and background noise.
- The probe achieves a 96% detection rate in a mouse model of peritoneal metastasis and enables complete resection of sub-millimeter lesions.
- GAP9 activates in tumors to provide T1-weighted MRI for preoperative mapping and NIR-II fluorescence for intraoperative guidance.

## Abstract

The nonspecific activation of activatable probes presents significant challenges in their applications for accurate cancer detection, leading to false signals in normal tissues and the potential oversight of microlesions. To address this issue, we developed a glutathione (GSH)‐activatable magnetic resonance imaging (MRI) and near‐infrared II (NIR‐II) fluorescent probe (GAP9) using a redox capacity engineering strategy. By systematically adjusting the reaction pH during probe synthesis, we could precisely modulate its oxidation capacity to ensure that the activation window of the probe precisely matched tumor GSH concentrations. This strategy ensures that GAP9 remains in the “OFF” state within normal tissues through dual MRI/NIR‐II quenching mechanisms, minimizing false‐positive signals and background noise. Upon reaching tumor sites, GAP9 undergoes GSH‐triggered disassembly, rapidly activating T1‐weighted MRI for preoperative tumor mapping and unlocking NIR‐II fluorescence for real‐time intraoperative tumor delineation. This tumor‐adaptable strategy enables the specific localization of microtumor lesions, intraoperative margin monitoring, and complete excision of ultrasmall residual foci ≤1 mm, achieving a 96% detection rate in a mouse model of peritoneal metastasis. This study presents a novel paradigm in molecular probe design, emphasizing the potential of integrating programmable redox chemistry with tumor‐specific characteristics to enhance detection accuracy, ultimately improving surgical outcomes and patient prognoses.

This study presents a glutathione (GSH)‐activatable dual‐modality probe (GAP9) with a redox‐tuned activation window for precise tumor detection. It remains quenched (“OFF”) in normal tissue yet activates specifically in tumors for T1‐weighted magnetic resonance imaging (MRI) preoperative mapping and near‐infrared II (NIR‐II) fluorescence intraoperative guidance, achieving >95% detection rate and complete resection of sub‐millimeter lesions.