Gene therapy,harnessing the power of CRISPR-Cas9 and/or DNAzyme systems,stands as a pivotal approach in cancer therapy,enabling the meticulous manipulation of genes pivotal to tumorigenesis and immunity.However,the pu...Gene therapy,harnessing the power of CRISPR-Cas9 and/or DNAzyme systems,stands as a pivotal approach in cancer therapy,enabling the meticulous manipulation of genes pivotal to tumorigenesis and immunity.However,the pursuit of precise gene therapy encounters formidable hurdles.Herein,a near-infrared upconversion theranostic nanomachine is devised and tailors for CRISPR-Cas9/DNAzyme systems mediate precise gene therapy.An ingenious logic DNAzyme system consists of Chain 1(C_(1))/Chain 2(C_(2))and endogenous lncRNA is designed.We employ manganese modified upconversion nanoparticles for carrying ultraviolet-responsive C_(1)-PC linker-C_(2)(C_(2)P)chain and Cas9 ribonucleoprotein(RNP),with outermost coats with hyaluronic acid.Upon reaching tumor microenvironment(TME),the released Mn^(2+)ions orchestrate a trifecta:facilitating endosomal escape,activating cGAS-STING signaling,and enabling T1-magnetic resonance imaging.Under near-infrared irradiation,Cas9 RNP/C_(2)P complex dissociates,releasing Cas9 RNP into the nucleus to perform gene editing of Ptpn2,while C_(1)/C_(2) chains self-assemble with endogenous lncRNA to form a functional DNAzyme system,targeting PD-L1 mRNA for gene silencing.This strategy remodels the TME by activating cGAS-STING signaling and dual immune checkpoints blockade,thus realizing tumor elimination.Our theranostic nanomachine armed with the CRISPR-Cas9/DNAzyme logic systems,represents a resourceful and promising strategy for advancing cancer systemic immunotherapy and precise gene therapy.展开更多
基金supported by the National Natural Science Foundation of China(82302365 and 32471475)Supporting project of Nanjing University of Chinese Medicine to NSFC(XPT82302365,China)+4 种基金Yangtze River Delta Joint Sci-tech Innovation and Research Projects(2023CSJZN0600,China)the Innovation Projects of State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture(NZYSKL240201,China)Jiangsu Key Discipline Construction Fund of the 14th Five-Year Plan(Biology)Natural Science Foundation of Hubei Province(No.2024AFB517,China)Natural Science Foundation of the Higher Education Institutions of Jiangsu Province(23KJB310015,China).
文摘Gene therapy,harnessing the power of CRISPR-Cas9 and/or DNAzyme systems,stands as a pivotal approach in cancer therapy,enabling the meticulous manipulation of genes pivotal to tumorigenesis and immunity.However,the pursuit of precise gene therapy encounters formidable hurdles.Herein,a near-infrared upconversion theranostic nanomachine is devised and tailors for CRISPR-Cas9/DNAzyme systems mediate precise gene therapy.An ingenious logic DNAzyme system consists of Chain 1(C_(1))/Chain 2(C_(2))and endogenous lncRNA is designed.We employ manganese modified upconversion nanoparticles for carrying ultraviolet-responsive C_(1)-PC linker-C_(2)(C_(2)P)chain and Cas9 ribonucleoprotein(RNP),with outermost coats with hyaluronic acid.Upon reaching tumor microenvironment(TME),the released Mn^(2+)ions orchestrate a trifecta:facilitating endosomal escape,activating cGAS-STING signaling,and enabling T1-magnetic resonance imaging.Under near-infrared irradiation,Cas9 RNP/C_(2)P complex dissociates,releasing Cas9 RNP into the nucleus to perform gene editing of Ptpn2,while C_(1)/C_(2) chains self-assemble with endogenous lncRNA to form a functional DNAzyme system,targeting PD-L1 mRNA for gene silencing.This strategy remodels the TME by activating cGAS-STING signaling and dual immune checkpoints blockade,thus realizing tumor elimination.Our theranostic nanomachine armed with the CRISPR-Cas9/DNAzyme logic systems,represents a resourceful and promising strategy for advancing cancer systemic immunotherapy and precise gene therapy.
