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.
DNA-based materials exhibit great potential in biomedical applications due to the excellent sequence programmability and unique functional designability. Rolling circle amplification (RCA) is an efficient isothermal enzymatic amplification strategy to...
Conspectus Developing a new system of material chemistry is an important molecular foundation for the design and preparation of functional materials, which resembles the preparation of raw materials such as bricks for constructing a building that determines the quality of the building. However, precisely controlling the synthesis processes and structures of functional materials always remains a grand challenge. It is expected to propose a paradigm of “gene-like” precise construction to realize the rational synthesis of functional materials, i.e., a “structure-function-application” principle for the precise construction. As the core genetic material of life, the DNA molecule is a bioactive macromolecule that can accurately encode genetic information and also can act as the generic molecular building block for the precise construction of functional materials. In this Account, we describe our work on the design and construction of functional DNA materials, to illustrate the principle of “gene-like” construction of functional DNA materials. The DNA molecule shows the unique advantages in the “gene-like” construction of functional materials, mainly including the precise arrangement of bases (monomers), the controllable design and assembly of structure, the precise transmission of sequence information, and customization of function. First, the number and sequence of four deoxynucleotide monomers that constitute the DNA strand can be rationally designed and accurately synthesized. Second, the sequence information on DNA endows the precise and efficient assembly of DNA molecules and ensures the precise regulation on the specific biological functions of functional DNA materials. Third, the functions of DNA materials can couple with the biological environments, so as to achieve the predetermined applications. Based on the scale of the constructed DNA materials, we categorize DNA materials into three classes: molecular scale, nanoscale, and macroscale. At the molecular scale, the representative material is branched DNA-based materials; the construction strategies mainly include target-triggered polymerization, enzymatic extension, and hybrid coupling; the applications mainly include the nonenzymatic detection of base mutation, the construction of artificial cells for the study of compartmentalization and the confinement effect, and the regulation of optical and antibacterial properties of supernanoclusters. At the nanoscale, the representative material is the DNA nanocomplex; the construction strategies mainly include hybridization with polymer, small molecule, and metal ions; the applications mainly include gene drug delivery and luminescence bioimaging. At the macroscale, the representative material is the DNA hydrogel; the construction strategies mainly include double-rolling circle amplification (double-RCA), multistage-RCA, and chemical cross-linking; the applications mainly include cell isolation, cell delivery, antibacterial agents, and self-healing electric circuits. Based on the “gene-like” paradigm, we expect to d...
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