DNA Nanoflowers Efficiently Encapsulate Photodynamic Agents and CRISPR/Cas9 for Synergistic Pancreatic Cancer Therapy
Nachuan Song1,2, Gengqi Tian2, Hongjin Li2
1Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200438, P.R. China.
Abstract:
Photodynamic therapy (PDT) holds significant promise for treating pancreatic cancer by utilizing photosensitizers to generate reactive oxygen species (ROS) that induce tumor cell death. However, the therapeutic efficacy of PDT is hindered by inadequate ROS accumulation. Herein, we develop a DNA nanoflower that enables the controlled codelivery of Cas9 ribonucleoprotein (RNP), hemin, and chlorin e6 for synergistic PDT. The Cas9 RNP selectively knocks out the antioxidant regulator nuclear factor E2-related factor 2 (Nrf2), thereby increasing cancer cells' sensitivity to ROS. Simultaneously, the G-quadruplex/hemin complex catalyzes the conversion of endogenous H2O2 into O2, alleviating tumor hypoxia and supplying additional oxygen for PDT. This synergistic approach substantially amplifies ROS accumulation by attenuating ROS elimination and enhancing ROS generation, demonstrating high gene editing efficiency, significant Nrf2 down-regulation, elevated apoptosis, and remarkable antitumor efficacy in pancreatic cancer cells and a mouse model, underscoring the potential for precision medicine.
Insights
This study presents a novel DNA nanoflower for pancreatic cancer treatment. It enhances photodynamic therapy (PDT) by boosting reactive oxygen species (ROS) for improved tumor cell death.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Photodynamic therapy (PDT) shows promise for pancreatic cancer but is limited by insufficient reactive oxygen species (ROS) accumulation.
- Overcoming ROS deficits is crucial for enhancing PDT efficacy in pancreatic cancer treatment.
Purpose of the Study:
- To develop a DNA nanoflower for synergistic photodynamic therapy (PDT) in pancreatic cancer.
- To enhance ROS accumulation by inhibiting ROS elimination and boosting ROS generation for improved therapeutic outcomes.
Main Methods:
- Codelivery of Cas9 ribonucleoprotein (RNP), hemin, and chlorin e6 using a DNA nanoflower.
- Utilizing Cas9 RNP to selectively knock out the antioxidant regulator Nrf2.
- Employing a G-quadruplex/hemin complex to convert H2O2 into O2, alleviating tumor hypoxia.
Main Results:
- Achieved high gene editing efficiency and significant Nrf2 down-regulation.
- Demonstrated substantial amplification of ROS accumulation through combined inhibition of elimination and enhancement of generation.
- Observed elevated apoptosis and remarkable antitumor efficacy in pancreatic cancer models.
Conclusions:
- The developed DNA nanoflower system effectively enhances synergistic PDT for pancreatic cancer.
- This approach shows significant potential for precision medicine applications in oncology.
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