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Published on: October 27, 2019
Spatiotemporally regulated mitochondrial genome editing via enzyme and NIR-activated CRISPR/Cas9 nanoplatform
Fei Yang1, Qianqin Ran1, Jiahui Chen1
1Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University Shanghai 200241 China yzxian@chem.ecnu.edu.cn clzhang@chem.ecnu.edu.cn.
Abstract:
Mitochondrial DNA (mtDNA) mutations play critical roles in tumor progression and metabolic reprogramming. Controllable gene editing within tumor cell mitochondria remains a challenge due to the double-membrane barrier and the lack of tumor-selective activation. Herein, we report a dual-responsive CRISPR/Cas delivery platform (UCRP-TPP) that enables spatiotemporally regulated mtDNA editing for targeted tumor therapy. This nanoplatform integrates near infrared light-responsive upconversion nanoparticle (UCNP), an apurinic endonuclease 1 (APE-1)-responsive DNA complex, and a mitochondrial-targeting ligand (TPP), ensuring selective activation and mitochondrial release of Cas9/sgRNA complexes. Upon activation by endogenous APE-1 enzyme and exogenous NIR light, UCRP-TPP induces mtDNA editing by CRISPR/Cas, which leads to mtDNA copy number reduction, mitochondrial membrane depolarization, reactive oxygen species generation, and tumor cell apoptosis. In vivo studies further confirm the robust antitumor efficacy of the UCRP-TPP-based nanoplatform. This work presents a versatile and controllable mitochondrial gene-editing strategy.
Insights
Researchers developed a dual-responsive CRISPR/Cas delivery platform for mitochondrial DNA editing in tumors. This nanoplatform enables targeted tumor therapy by precisely editing mitochondrial DNA, reducing tumor cell viability.
Area of Science:
- Biomedical Engineering
- Molecular Biology
- Cancer Research
Background:
- Mitochondrial DNA (mtDNA) mutations are crucial in tumor progression and metabolic changes.
- Targeted gene editing within tumor mitochondria is difficult due to cellular barriers and lack of tumor-specific activation.
Purpose of the Study:
- To develop a controllable, dual-responsive CRISPR/Cas delivery platform for spatiotemporally regulated mtDNA editing in tumors.
- To enable targeted tumor therapy through precise mitochondrial gene editing.
Main Methods:
- Designed a nanoplatform (UCRP-TPP) integrating upconversion nanoparticles (UCNP), an APE-1-responsive DNA complex, and a mitochondrial-targeting ligand (TPP).
- Utilized endogenous APE-1 enzyme and exogenous near-infrared (NIR) light for selective activation and mitochondrial release of Cas9/sgRNA.
- Induced mtDNA editing via CRISPR/Cas system upon dual activation.
Main Results:
- Demonstrated reduction in mtDNA copy number and mitochondrial membrane depolarization.
- Showcased increased reactive oxygen species generation and induced tumor cell apoptosis.
- Confirmed robust antitumor efficacy through in vivo studies.
Conclusions:
- The UCRP-TPP nanoplatform provides a versatile and controllable strategy for mitochondrial gene editing.
- This approach offers a promising avenue for targeted tumor therapy by exploiting mtDNA editing.
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