The development of self-assembled DNA nanomedicine requires a facile and accurate DNA degradation strategy for precisely programmable drug release. Conventional DNA catabolic strategies are restrained with the fragile and unclear enzymatic reactions that might lead to inefficient and uncontrollable digestion of DNA scaffolds and thus might bring undesirable side effects to the sophisticated biosystems. Herein we reported a versatile selfsufficient DNAzyme-driven drug delivery system consisting of the rolling circle polymerized DNAzyme−substrate scaffolds and the encapsulated pH-responsive ZnO nanoparticles (NPs). The full DNAzyme nanosponges (NSs) were also encoded with multivalent tandem aptamer sequences to facilitate their efficient delivery into cancer cells, where the acidic endo/lysosomal microenvironment stimulates the dissolution of ZnO into Zn 2+ ions as DNAzyme cofactors and therapeutic reactive oxygen species generators. The supplement Zn 2+ cofactors mediated the nonviolent DNAzyme-catalyzed cleavage of DNA scaffolds for precise and efficient drug administrations with synergistically enhanced therapeutic performance. The facile design of DNAzyme, together with their cost-effective and intrinsic robust features, is anticipated to provide extensive insights for the development of DNA-based therapeutic platforms by activating the specific intracellular biocatalytic reactions. As an intelligent and nonviolent self-driven drug delivery platform, the present DNAzyme NS system could be engineered with more therapeutic sequences and agents and was anticipated to show exceptional promise and versatility for applications in biomedicine and bioengineering.

A reconfigurable hybridization-based chain reaction was introduced to assemble enzyme-free DNA logic gates and advanced logic circuits for analyzing multiple endogenous miRNA expressions and discriminating different living cells.

The therapeutic performance of DNAzyme-involved gene silencing is significantly constrained by inefficient conditional activation and insufficient cofactor supply.Herein, as elf-sufficient therapeutic nanosystem was realized through the delicate design of DNAzyme prodrugs and MnO 2 into abiocompatible nanocapsule with tumor-specific recognition/ activation features.T he indocyanine green (ICG)-modified DNAp rodrugs are designed by splitting the DNAzyme and then reconstituted into the exquisite catalyzed hairpin assembly (CHA) amplification circuit. Based on the photothermal activation of ICG,the nanocapsule was disassembled to expose the MnO 2 ingredient whichwas immediately decomposed into Mn 2+ ions to supplement an indispensable DNAzyme cofactor on-demand with ac oncomitant O 2 generation for enhancing the auxiliary phototherapy. The endogenous microRNAc atalyzes the amplified assembly of DNAprodrugs via an exquisite CHA principle,l eading to the DNAzyme-mediated simultaneous silencing of two key tumor-involved mRNAs.T his selfactivated theranostic nanocapsule could substantially expand the toolbox for accurate diagnosis and programmable therapeutics.

An on-site bioorthogonal regulated DNA circuit was developed by introducing an endogenous DNA repairing enzyme-mediated sequential activation strategy to achieve cancer cell-selective microRNA imaging with high anti-interference ability.

chiral sensors that achieve the reliable exploration of intracellular biosensing events. [5] Despite the prevalence of chirality in biology, chiral supramolecular assembly structures have been rarely exploited to facilitate drug delivery and achieve specific biological regulation in vivo. It is expected that these nanoparticles could facilitate the stereospecific induction of cancer cell death through apoptosis or autophagy. [6] Recently, chiral nanomaterials have also been fabricated for biomimetic catalysis by virtue of their advantages of precise structural design, and high reactivity and stereoselectivity. [7] However, no attempts have been made on the extensive utilization of chiral catalysisassociated therapy, which can be largely attributed to the inefficient biocatalysis in complex cytoplasmic environments. Therefore, it is highly desirable to develop a robust chiral biocatalysis system for disease therapeutics.As a chiral biomimetic catalyst, DNAzymes can specifically and efficiently cleave their corresponding substrate. [8] Based on their unique cofactor-dependent, sequence-specific, and programmable biocatalysis, DNAzymes have attracted increasing attention as therapeutic agents for gene silencing utilities. [9] However, the intelligent therapeutic application of l-DNAzyme is constrained by several challenges. The first key issue is the high susceptibility of natural right-handed d-DNA to ubiquitous nucleases. Alternatively, l-DNA, as the enantiomer of d-DNA, can resist nuclease digestion in the absence of stereospecific interaction with nuclease, thus exhibiting excellent stability in vivo. [10] Especially, l-DNA is impervious to intrinsic DNA hybridization and catalysis function. [11] The second key issue is the inefficient DNAzyme delivery/release and insufficient cofactors supply. [12] Such limitations are addressed through the emergence of biomolecules-ZIF-8 composites as a smart self-driven nanocarrier. We have previously reported that the pH-responsive ZIF-8 can deliver and release functional DNA to tumor cells. [13] However, the release efficiency is limited in an acidic microenvironment and can cause insufficient DNAzyme activation and unwanted metal-ion DNAzyme cofactor cytotoxicity, thus requiring the fine adjustment of nanocomposite dosage. Alternatively, adenosine triphosphate (ATP), a primary energy source in living organisms, is also used as an activity regulator in many cellular processes. [14] The intracellular cytosol ATP (1-10 mm) is usually elevated than that in the extracellular Programmable chiral biocatalysis represents a promising therapeutic strategy for its high stereospecific control over various biotransformations (e.g., chiral Aβ isomerization) of living entities yet is rarely explored. With an extraordinary resistance to nuclease digestion, the non-natural left-handed deoxyribozyme (l-DNAzyme) therapy is constrained by inefficient delivery/release and insufficient cofactors supply. Herein, an efficient adenosine triphosphate (ATP)-stimulated disassembly of l-histi...

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Isothermal autocatalytic DNA circuits have been proven to be versatile and powerful biocomputing platforms by virtue of their self-sustainable and self-accelerating reaction profiles, yet they are currently constrained by their complicated designs, severe signal leakages, and unclear reaction mechanisms. Herein, we developed a simpler-yet-efficient autocatalytic assembly circuit (AAC) for highly robust bioimaging in live cells and mice. The scalable and sustainable AAC system was composed of a mere catalytic DNA assembly reaction with minimal strand complexity and, upon specific stimulation, could reproduce numerous new triggers to expedite the whole reaction. Through in-depth theoretical simulations and systematic experimental demonstrations, the catalytic efficiency of these reproduced triggers was found to play a vital role in the autocatalytic profile and thus could be facilely improved to achieve more efficient and characteristic autocatalytic signal amplification. Due to its exponentially high signal amplification and minimal reaction components, our self-stacking AAC facilitated the efficient detection of trace biomolecules with low signal leakage, thus providing great clinical diagnosis and therapeutic assessment potential.

High mortality and rapid development of metastasis requires the development of more effective antimetastasis strategies. However, conventional therapeutic methods, including surgery, radiation therapy, and chemotherapy, show less effectiveness in curbing the metastatic spread of cancer cells and the formation of metastases. A therapeutic platform, targeting the early stage of metastasis cascade, could effectively prevent metastasis dissemination. Herein, Fe/Mn-based metal–organic frameworks (FMM) were constructed for the delivery of a specific DNAzyme with high catalytic cleavage activity on the metastasis-involved Twist mRNA, thus efficiently inhibiting the invasion of cancer cells through DNAzyme-catalyzed gene silencing. Highly potent combined gene/chemodynamic therapy is achieved from the self-supplied DNAzyme cofactors and efficient glutathione depletion. Importantly, by virtue of the intrinsic photo-to-thermal conversion of the FMM nanocarriers, our combined therapeutic strategy could be further promoted under photothermal stimuli to speed up the Fenton reaction and to accelerate the release of the Twist DNAzyme with efficient gene therapy. Consequently, the effective elimination of tumors and the blockage of metastasis are simultaneously achieved under photothermal/magnetic resonance imaging guidance. This work aims at developing versatile theranostic agents to combat metastatic tumors.