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.
Multidrug resistance (MDR) in cancer cells is a substantial limitation to the success of chemotherapy. The spatio-temporal controlled gene-chemo therapeutics strategy is expected to surmount the limitation of MDR. We herein develop a DNA nanocomplex to achieve intrinsic stimuli-responsive spatio-temporal controlled gene-chemo drug delivery, overcoming MDR of cancer cells. The drug delivery system consisted of a restriction endonuclease (HhaI)-degradable DNA hydrogel layer, an acid-responsive HhaI nanocapsule (HhaI-GDA), and a glutathione (GSH)-sensitive dendritic mesoporous organosilica nanoparticle (DMON). The DNA hydrogel layer consisted of a DNA network formed through interfacial assembly from ultralong single-stranded DNA (ssDNA), which contained multiple tandem repeated antisense oligonucleotides (ASOs). DMON had dendritic mesopores for enhanced loading of anti-tumor drug doxorubicin (DOX). Upon cellular uptake of the DNA nanocomplex, the GDA shell was degraded at a lysosomal microenvironment, and the activity of HhaI was activated, leading to accurate cleavage ultralong ssDNA to release ASO as gene drugs, which downregulated the expression of MDR-related P glycoprotein. Spatio-temporal sequentially, DMONs containing disulfide bonds responded to intracellular GSH to release DOX for enhanced chemotherapy.
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.
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