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Tumor Microenvironment Activated Cu Crosslinked Near-Infrared Sonosensitizers for Visualized Cuproptosis-Enhanced
Jinyan Hu1, Lang Yan1, Zhi Cao2
1Department of Health Toxicology, College of Naval Medicine, Naval Medical University, Shanghai, 200433, China.
Abstract:
Reactive oxygen species (ROS)-mediated sonodynamic therapy (SDT) holds increasing potential in treating deep-seated tumor owing to the high tissue-penetration depth. However, the inevitable accumulation of sonosensitizers in normal tissues not only make it difficult to realize the in situ SDT, but also induces sonodynamic effects in normal tissues. Herein, this work reports the passivation and selective activation strategies for the sonodynamic and near-infrared (NIR) imaging performances of an intelligent antitumor theranostic platform termed Cu-IR783 nanoparticles (NPs). Owing to the ruptured coordination bond between IR783 with Cu ions by responding to tumor microenvironment (TME), the selective activation of IR783 only occurred in tumor tissues to achieve the visualized in-situ SDT. The tumor-specific released Cu ions not only realized the cascade amplification of ROS generation through Cu+-mediated Fenton-like reaction, but also triggered cuproptosis through Cu+-induced DLAT oligomerization and mitochondrial dysfunction. More importantly, the immunosuppressive TME can be reversed by the greatly enhanced ROS levels and high-efficiency cuproptosis, ultimately inducing immunogenic cell death that promotes robust systemic immune responses for the eradication of primary tumors and suppression of distant tumors. This work provides a distinct paradigm of the integration of SDT, CDT, and cuproptosis in a controlled manner to achieve visualized in-situ antitumor therapy.
Insights
This study introduces Cu-IR783 nanoparticles for targeted sonodynamic therapy (SDT). These nanoparticles selectively activate in tumors, enhancing reactive oxygen species (ROS) generation and triggering cell death for effective cancer treatment.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Sonodynamic therapy (SDT) shows promise for deep-seated tumors due to high tissue penetration.
- Current SDT faces challenges with sonosensitizer accumulation in normal tissues, leading to off-target effects.
- Developing targeted theranostic platforms is crucial for effective and safe in situ tumor treatment.
Purpose of the Study:
- To develop an intelligent theranostic platform, Cu-IR783 nanoparticles (NPs), for selective activation and visualized in situ sonodynamic therapy (SDT).
- To investigate the combined therapeutic effects of SDT, chemodynamic therapy (CDT), and cuproptosis.
- To explore the reversal of the immunosuppressive tumor microenvironment (TME) and induction of systemic anti-tumor immunity.
Main Methods:
- Fabrication of Cu-IR783 nanoparticles with a tumor microenvironment (TME)-responsive coordination bond.
- Utilizing the TME to trigger selective activation of IR783 for visualized in situ SDT.
- Investigating Cu+-mediated Fenton-like reactions for reactive oxygen species (ROS) amplification.
- Analyzing Cu+-induced cuproptosis via DLAT oligomerization and mitochondrial dysfunction.
- Evaluating the reversal of immunosuppressive TME and induction of immunogenic cell death.
Main Results:
- Cu-IR783 NPs demonstrated selective activation in the TME, enabling visualized in situ SDT.
- Tumor-specific release of Cu ions led to cascade amplification of ROS and triggered cuproptosis.
- Enhanced ROS levels and cuproptosis reversed the immunosuppressive TME.
- The theranostic platform induced immunogenic cell death, promoting robust systemic immune responses against primary and distant tumors.
Conclusions:
- The developed Cu-IR783 NPs offer a novel strategy for targeted antitumor theranostics.
- The integration of SDT, CDT, and cuproptosis in a controlled manner provides a powerful approach for visualized in situ cancer therapy.
- This work presents a distinct paradigm for overcoming limitations in current SDT and enhancing anti-tumor immunity.
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