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Photoactivatable Cascade DNAzyme Nanomachines for Amplified Imaging of Tumor Response to STING-Activated
Jiajia Pan1, Haojie Wu1, Yunxuan Chou1
1School of Environmental & Chemical Engineering, Jiangsu University of Science and Technology, Changhui Rd. 666, Zhenjiang, Jiangsu 212003, China.
Abstract:
Real-time monitoring of enzymatic cascades following Stimulator of Interferon Genes (STING) activation is vital for elucidating the mechanisms and efficacy of cancer immunotherapies. However, the concurrent visualization of multiple enzymatic targets in vivo remains restricted by insufficient specificity and sensitivity. Herein, we report a near-infrared (NIR) photoactivatable cascade DNAzyme nanomachine (PCDzNM) designed for the concurrent, amplified imaging of granzyme B (Gzm B) and cathepsin B (Cat B) activity during STING-activated immunotherapy. In this platform, DNAzymes are initially caged by protease-substrate peptides. Upon NIR irradiation, these peptides are cleaved by their target proteases, restoring DNAzyme activity and initiating a site-specific substrate cleavage that amplifies fluorescence signals in situ. Both in vitro and in vivo evaluations demonstrate that this spatiotemporally controlled PCDzNM enables precise, real-time visualization of enzyme dynamics. Notably, we observed divergent enzymatic profiles: immune-suppressed tumor microenvironments exhibit high Cat B but low Gzm B activity, whereas STING-activated tumors display the reverse pattern. This platform represents a robust tool for real-time monitoring immune-tumor interactions and holds potential for guiding personalized immunotherapy.
Insights
This study introduces a novel nanomachine for real-time imaging of enzyme activity during cancer immunotherapy. It visualizes granzyme B and cathepsin B dynamics, revealing distinct patterns in different tumor environments.
Area of Science:
- Biomedical Engineering
- Molecular Imaging
- Cancer Immunotherapy
Background:
- Real-time monitoring of enzymatic activity is crucial for understanding cancer immunotherapies.
- Current methods lack specificity and sensitivity for concurrent in vivo visualization of multiple enzymes.
Purpose of the Study:
- To develop a photoactivatable cascade DNAzyme nanomachine (PCDzNM) for simultaneous, amplified imaging of granzyme B (Gzm B) and cathepsin B (Cat B) activity.
- To enable precise, real-time visualization of enzyme dynamics during Stimulator of Interferon Genes (STING)-activated immunotherapy.
Main Methods:
- Designed a NIR photoactivatable cascade DNAzyme nanomachine (PCDzNM) with protease-substrate caged DNAzymes.
- Utilized NIR irradiation to activate DNAzymes upon target protease cleavage, initiating amplified fluorescence signaling.
- Performed in vitro and in vivo evaluations to assess spatiotemporal control and enzyme visualization.
Main Results:
- The PCDzNM platform achieved concurrent, amplified imaging of Gzm B and Cat B activity.
- Demonstrated precise, real-time visualization of enzyme dynamics in vitro and in vivo.
- Observed distinct enzymatic profiles: high Cat B/low Gzm B in immune-suppressed tumors, and low Cat B/high Gzm B in STING-activated tumors.
Conclusions:
- The developed PCDzNM is a robust tool for real-time monitoring of immune-tumor interactions.
- Revealed divergent enzyme activity patterns correlating with tumor immune status.
- This platform holds potential for guiding personalized cancer immunotherapy strategies.
