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Sono-Controllable and ROS-Sensitive CRISPR-Cas9 Genome Editing for Augmented/Synergistic Ultrasound Tumor Nanotherapy
Yinying Pu1, Haohao Yin1, Caihong Dong2
1Center of Minimally Invasive Treatment for Tumor, Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, School of Medicine, Tongji University, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, Shanghai, 200072, China.
Abstract:
The potential of the cluster regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9)-based therapeutic genome editing is severely hampered by the difficulties in precise regulation of the in vivo activity of the CRISPR-Cas9 system. Herein, sono-controllable and reactive oxygen species (ROS)-sensitive sonosensitizer-integrated metal-organic frameworks (MOFs), denoted as P/M@CasMTH1, are developed for augmented sonodynamic therapy (SDT) efficacy using the genome-editing technology. P/M@CasMTH1 nanoparticles comprise singlet oxygen (1 O2 )-generating MOF structures anchored with CRISPR-Cas9 systems via 1 O2 -cleavable linkers, which serve not only as a delivery vector of CRISPR-Cas9 targeting MTH1, but also as a sonoregulator to spatiotemporally activate the genome editing. P/M@CasMTH1 escapes from the lysosomes, harvests the ultrasound (US) energy and converts it into abundant 1 O2 to induce SDT. The generated ROS subsequently trigger cleavage of ROS-responsive thioether bonds, thus inducing controllable release of the CRISPR-Cas9 system and initiation of genome editing. The genomic disruption of MTH1 conspicuously augments the therapeutic efficacy of SDT by destroying the self-defense system in tumor cells, thereby causing cellular apoptosis and tumor suppression. This therapeutic strategy for synergistic MTH1 disruption and abundant 1 O2 generation provides a paradigm for augmenting SDT efficacy based on the emerging nanomedicine-enabled genome-editing technology.
Insights
This study introduces P/M@CasMTH1 nanoparticles for precise CRISPR-Cas9 genome editing activation via ultrasound. This approach enhances sonodynamic therapy (SDT) by disrupting tumor cell defenses, leading to apoptosis and tumor suppression.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Genome Editing
Background:
- CRISPR-Cas9 genome editing offers therapeutic potential but faces challenges in precise in vivo activity regulation.
- Sonodynamic therapy (SDT) is an emerging cancer treatment modality that utilizes ultrasound to generate reactive oxygen species (ROS).
Purpose of the Study:
- To develop sono-controllable and ROS-sensitive nanoparticles (P/M@CasMTH1) for augmented SDT efficacy through genome editing.
- To investigate the synergistic effect of MTH1 gene disruption and ROS generation on tumor cell apoptosis and suppression.
Main Methods:
- P/M@CasMTH1 nanoparticles were synthesized, integrating a singlet oxygen-generating metal-organic framework (MOF) with CRISPR-Cas9 systems via ROS-cleavable linkers.
- Nanoparticles were designed to deliver CRISPR-Cas9 targeting MTH1 and act as a sonoregulator, releasing the genome editing system upon ultrasound (US) exposure and subsequent ROS generation.
- The therapeutic efficacy was evaluated by assessing MTH1 gene disruption, ROS production, cellular apoptosis, and tumor suppression.
Main Results:
- P/M@CasMTH1 nanoparticles successfully harvested ultrasound energy, generating abundant singlet oxygen (1 O2) for SDT.
- Generated ROS triggered the cleavage of ROS-responsive linkers, leading to controlled release of CRISPR-Cas9 and subsequent MTH1 gene editing.
- Genomic disruption of MTH1 enhanced SDT efficacy by compromising tumor cell self-defense mechanisms, resulting in increased apoptosis and significant tumor suppression.
Conclusions:
- The developed P/M@CasMTH1 nanoparticles provide a spatiotemporally controlled platform for genome editing activation via ultrasound.
- This synergistic approach combining MTH1 disruption with enhanced 1 O2 generation offers a novel strategy for augmenting SDT efficacy.
- This nanomedicine-enabled genome-editing technology presents a promising paradigm for advanced cancer therapy.
Related Concept Videos
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01:59CRISPR
02:31Homologous Recombination
02:53CRISPR and crRNAs
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