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An Integrated System to Remotely Trigger Intracellular Signal Transduction by Upconversion Nanoparticle-mediated Kinase Photoactivation
Published on: August 30, 2017
Mitochondria-to-Nucleus Trafficking NIR-II Type I AIE Photosensitizer Synergistically Activates cGAS-STING Pathway
Caixia Ma1, Jiabao Zhuang1, Jia Jia1
1Key Laboratory of Applied Surface and Colloid Chemistry of Ministry of Education, Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an, 710119, P. R. China.
Abstract:
Activating the cGAS-STING signaling axis has emerged as a promising therapeutic strategy for combating tumor proliferation. However, conventional cGAS-STING agonists are hindered by the lack of precision in organelle targeting and limited capacity to induce DNA damage, impeding their therapeutic efficacy. Herein, it is developed a mitochondria-to-nucleus trafficking near-infrared II (NIR-II) type I photosensitizer (MPTB) for the synergistic activation of the cGAS-STING pathway. The incorporation of the N,N-dimethylamino tetraphenylethene substituent, an electron-donating moiety with conformational distortion, finely tuned the radiative and non-radiative decay of MPTB, endowing it with exceptional NIR-II emission properties, robust type I reactive oxygen species (ROS) generation capacity, and remarkable photothermal conversion efficiency (63.6%). The lipocationic nature of MPTB facilitated its precise accumulation in mitochondria. Upon irradiation with 635 nm laser, MPTB-mediated phototherapy caused damage to mitochondrial DNA (mtDNA). Subsequently, MPTB translocated to the nucleus, resulting in the impairment of nuclear DNA (nDNA). This synergistic mtDNA and nDNA damage led to an increased release of DNA fragments, which efficiently activated the cGAS-STING signaling pathway and triggered immunogenic cell death, thereby enhancing the therapeutic efficacy. The formulated MPTB nanoparticles demonstrated intense NIR-II fluorescence/photothermal imaging capabilities in vivo, enabling precise imaging-guided phototherapy to suppress tumor proliferation with minimal off-target effects.
Insights
A novel photosensitizer precisely targets mitochondria and nucleus, causing DNA damage to activate the cGAS-STING pathway for enhanced cancer immunotherapy. This approach improves tumor suppression with minimal side effects.
Area of Science:
- Biomedical Engineering
- Photodynamic Therapy
- Cancer Immunotherapy
Background:
- The cGAS-STING pathway is a promising target for cancer therapy, but current agonists lack organelle specificity and DNA-damaging capacity.
- Tumor proliferation necessitates novel therapeutic strategies with improved targeting and efficacy.
Purpose of the Study:
- To develop a mitochondria-targeting photosensitizer (MPTB) for synergistic activation of the cGAS-STING pathway.
- To enhance phototherapy efficacy through precise organelle targeting and dual DNA damage induction.
Main Methods:
- Synthesis of a near-infrared II (NIR-II) type I photosensitizer (MPTB) with lipocationic properties.
- Utilizing MPTB for mitochondria-to-nucleus trafficking and subsequent phototherapy upon 635 nm laser irradiation.
- Evaluating MPTB's NIR-II emission, reactive oxygen species (ROS) generation, photothermal conversion, and in vivo imaging capabilities.
Main Results:
- MPTB demonstrated efficient NIR-II emission, ROS generation, and photothermal conversion (63.6%).
- MPTB precisely accumulated in mitochondria, causing mitochondrial DNA (mtDNA) damage, followed by nuclear translocation and nuclear DNA (nDNA) damage.
- Synergistic DNA damage activated the cGAS-STING pathway, triggered immunogenic cell death, and suppressed tumor growth in vivo with minimal off-target effects.
Conclusions:
- MPTB enables precise, synergistic activation of the cGAS-STING pathway via dual mtDNA and nDNA damage.
- MPTB nanoparticles offer advanced NIR-II fluorescence/photothermal imaging for guided phototherapy.
- This strategy presents a potent approach for imaging-guided cancer immunotherapy with enhanced therapeutic outcomes.
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