Copper-based nanomaterials demonstrate promising potential in cancer therapy.Cut efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione,initiating chemical dynamic therapy(CDT)a...Copper-based nanomaterials demonstrate promising potential in cancer therapy.Cut efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione,initiating chemical dynamic therapy(CDT)and ferroptosis.Cuproptosis,a newly identified cell death modality that represents a great prospect in cancer therapy,is activated.However,active homeostatic systems rigorously keep copper levels within cells exceptionally low,which hinders the application of cooper nanomaterials-based therapy.Herein,a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed.The Cu2O and organosilica shell would degrade under the high level of glutathione and weak acidic environment,further releasing RNP and Cut.The liberated Cut triggered a Fenton-like reaction for CDT and partially transformed to Cu2t,consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently.Meanwhile,the release of RNP effectively reduced the expression of copper transporter ATP7A,subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT,cuproptosis,and ferroptosis.Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.展开更多
基金the National Natural Science Foundation of China(82374287,82174466,81930117)National Key Research and Development Project(2022YFC3500200,China)+3 种基金Key research and development projects of Ningxia(Grant No.2021BEG02040,China)Natural Science Foundation Project of Jiangsu Province(BK20211390,China)Open Projects of the Discipline of Chinese Medicine of Nanjing University of Chinese Medicine Supported by the Subject of Academic priority discipline of Jiangsu Higher Education Institutions,Program for Leading Talents of Traditional Chinese Medicine of Jiangsu Province(SLJ0314)Blue Project of Jiangsu province.
文摘Copper-based nanomaterials demonstrate promising potential in cancer therapy.Cut efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione,initiating chemical dynamic therapy(CDT)and ferroptosis.Cuproptosis,a newly identified cell death modality that represents a great prospect in cancer therapy,is activated.However,active homeostatic systems rigorously keep copper levels within cells exceptionally low,which hinders the application of cooper nanomaterials-based therapy.Herein,a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed.The Cu2O and organosilica shell would degrade under the high level of glutathione and weak acidic environment,further releasing RNP and Cut.The liberated Cut triggered a Fenton-like reaction for CDT and partially transformed to Cu2t,consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently.Meanwhile,the release of RNP effectively reduced the expression of copper transporter ATP7A,subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT,cuproptosis,and ferroptosis.Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.
