Sequential control of exogenous chemical events inside cells is ap romising wayt or egulate cell functions and fate.H erein we report aD NA nanocomplex containing cascade DNAzymes and promoter-like Zn-Mn-Ferrite (ZMF), achieving combined gene/chemo-dynamic therapy. The promoter-like ZMF decomposed in response to intratumoral glutathione to release as ufficient quantity of metal ions,t hus promoting cascade DNA/RNAc leavage and free radical generation. Tw okinds of DNAzymes were designed for sequential cascade enzymatic reaction, in whichm etal ions functioned as cofactors.T he primary DNAzyme self-cleaved the DNAc hain with Zn 2+ as cofactor,a nd produced the secondary DNAzyme;t he secondary DNAzyme afterwards cleaved the EGR-1 mRNA, and thus downregulated the expression of target EGR-1 protein, achieving DNAzymebased gene therapy. Meanwhile,t he released Zn 2+ ,M n 2+ and Fe 2+ induced Fenton/Fenton-like reactions,d uring which free radicals were catalytically generated and efficient chemodynamic therapyw as achieved. In ab reast cancer mouse model, the administration of DNAn anocomplex led to asignificant therapeutic efficacy of tumor growth suppression.

Intracellular accumulation of reactive oxygen species (ROS) leads to oxidative stress, which is closely associated with many diseases. Introducing artificial organelles to ROS-imbalanced cells is a promising solution, but this route requires nanoscale particles for efficient cell uptake and micro-scale particles for long-term cell retention, which meets a dilemma. Herein, we report a deoxyribonucleic acid (DNA)-ceria nanocomplex-based dynamic assembly system to realize the intracellular in-situ construction of artificial peroxisomes (AP). The DNA-ceria nanocomplex is synthesized from branched DNA with i-motif structure that responds to the acidic lysosomal environment, triggering transformation from the nanoscale into bulk-scale AP. The initial nanoscale of the nanocomplex facilitates cellular uptake, and the bulk-scale of AP supports cellular retention. AP exhibits enzyme-like catalysis activities, serving as ROS eliminator, scavenging ROS by decomposing H2O2 into O2 and H2O. In living cells, AP efficiently regulates intracellular ROS level and resists GSH consumption, preventing cells from redox dyshomeostasis. With the protection of AP, cytoskeleton integrity, mitochondrial membrane potential, calcium concentration and ATPase activity are maintained under oxidative stress, and thus the energy of cell migration is preserved. As a result, AP inhibits cell apoptosis, reducing cell mortality through ROS elimination.

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Sequential control of exogenous chemical events inside cells is ap romising wayt or egulate cell functions and fate.H erein we report aD NA nanocomplex containing cascade DNAzymes and promoter-like Zn-Mn-Ferrite (ZMF), achieving combined gene/chemo-dynamic therapy. The promoter-like ZMF decomposed in response to intratumoral glutathione to release as ufficient quantity of metal ions,t hus promoting cascade DNA/RNAc leavage and free radical generation. Tw okinds of DNAzymes were designed for sequential cascade enzymatic reaction, in whichm etal ions functioned as cofactors.T he primary DNAzyme self-cleaved the DNAc hain with Zn 2+ as cofactor,a nd produced the secondary DNAzyme;t he secondary DNAzyme afterwards cleaved the EGR-1 mRNA, and thus downregulated the expression of target EGR-1 protein, achieving DNAzymebased gene therapy. Meanwhile,t he released Zn 2+ ,M n 2+ and Fe 2+ induced Fenton/Fenton-like reactions,d uring which free radicals were catalytically generated and efficient chemodynamic therapyw as achieved. In ab reast cancer mouse model, the administration of DNAn anocomplex led to asignificant therapeutic efficacy of tumor growth suppression.