Programmably tiling rigidified DNA brick on gold nanoparticle as multi-functional shell for cancer-targeted delivery of siRNAs

Xue, Chang; Hu, Shuyao; Gao, Zhihua; Wang, Lei; Luo, Mengxue; Yu, Xin; Li, Bifei; Shen, Zhifa; Wu, Zai‐Sheng

doi:10.1038/s41467-021-23250-5

Cited by 72 publications

(40 citation statements)

References 64 publications

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“…According to literature reports, ,, a DNAzyme may be split into two halves or separated by inserting target-binding fragment in the middle and its catalytic activity can be restored when target species bring the two components together. Moreover, hiding the terminals of oligonucleotide components from nuclease attack and rigidifying DNA nanostructures can substantially enhance the resistance to nuclease degradation. − Inspired by these advances in improving DNAzyme-based sensing probes and enhancing degradation resistance of DNA assemblies, we sought to demonstrate ES-AuNP nanoprobe for imaging of miRNAs in living cells and even in living organisms whose key component is a specifically adapted nuclease-resistant DNAzyme walker (E). The design of ES-AuNP nanoprobe and working principle of DNAzyme walker for miRNA detection are shown in the left panel and right panel in Scheme A, respectively.…”

Section: Results and Discussionmentioning

confidence: 99%

Self-Protected DNAzyme Walker with a Circular Bulging DNA Shield for Amplified Imaging of miRNAs in Living Cells and Mice

Gao

Zhang

et al. 2021

ACS Nano

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Abnormal expression of miRNAs is often detected in various human cancers. DNAzyme machines combined with gold nanoparticles (AuNPs) hold promise for detecting specific miRNAs in living cells but show short circulation time due to the fragility of catalytic core. Using miRNA-21 as the model target, by introducing a circular bulging DNA shield into the middle of the catalytic core, we report herein a self-protected DNAzyme (E) walker capable of fully stepping on the substrate (S)-modified AuNP for imaging intracellular miRNAs. The DNAzyme walker exhibits 5-fold enhanced serum resistance and more than 8-fold enhanced catalytic activity, contributing to the capability to image miRNAs much higher than commercial transfection reagent and well-known FISH technique. Diseased cells can accurately be distinguished from healthy cells. Due to its universality, DNAzyme walker can be extended for imaging other miRNAs only by changing target binding domain, indicating a promising tool for cancer diagnosis and prognosis.

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Section: Results and Discussionmentioning

confidence: 99%

Self-Protected DNAzyme Walker with a Circular Bulging DNA Shield for Amplified Imaging of miRNAs in Living Cells and Mice

Gao

Zhang

et al. 2021

ACS Nano

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“…Intriguingly, some miRNAs delivered systemically by nanoparticle or alternative carriers exhibit obvious treatment effects on cancer with relatively high specificity in targeting tumor cells. [19][20][21][22] Moreover, some clinical trials reveal that miRNAs-based mimic drugs have potent antitumor capacity and a subset of patients can gain encouraging responses (NCT04675996 and NCT02369198). [23][24][25][26] Therefore, the employment of nanoparticle-based delivery of candidate miRNAs in the regulation of ferroptosis might be a promising synergistic approach for cancer immunotherapy, but the roles of miRNAs in anti-PD-1 immunotherapy-associated ferroptosis, as well as their therapeutic effect on melanoma, should be thoroughly investigated.…”

Section: Key Messagesmentioning

confidence: 99%

Nanoparticle delivery of miR-21-3p sensitizes melanoma to anti-PD-1 immunotherapy by promoting ferroptosis

Guo

Chen

et al. 2022

J Immunother Cancer

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BackgroundAlthough anti-programmed cell death protein 1 (PD-1) immunotherapy is greatly effective in melanoma treatment, low response rate and treatment resistance significantly hinder its efficacy. Tumor cell ferroptosis triggered by interferon (IFN)-γ that is derived from tumor-infiltrating CD8+ T cells greatly contributes to the effect of immunotherapy. However, the molecular mechanism underlying IFN-γ-mediated ferroptosis and related potentially promising therapeutic strategy warrant further clarification. MicroRNAs (miRNAs) participate in ferroptosis execution and can be delivered systemically by multiple carriers, which have manifested obvious therapeutic effects on cancer.MethodsMiRNAs expression profile in IFN-γ-driven ferroptosis was obtained by RNA sequencing. Biochemical assays were used to clarify the role of miR-21-3p in IFN-γ-driven ferroptosis and the underlying mechanism. MiR-21-3p-loaded gold nanoparticles were constructed and systemically applied to analyze the role of miR-21-3p in anti-PD-1 immunotherapy in preclinical transplanted tumor model.ResultsMiRNAs expression profile of melanoma cells in IFN-γ-driven ferroptosis was first obtained. Then, upregulated miR-21-3p was proved to facilitate IFN-γ-mediated ferroptosis by potentiating lipid peroxidation. miR-21-3p increased the ferroptosis sensitivity by directly targeting thioredoxin reductase 1 (TXNRD1) to enhance lipid reactive oxygen species (ROS) generation. Furthermore, miR-21-3p overexpression in tumor synergized with anti-PD-1 antibody by promoting tumor cell ferroptosis. More importantly, miR-21-3p-loaded gold nanoparticles were constructed, and the systemic delivery of them increased the efficacy of anti-PD-1 antibody without prominent side effects in preclinical mice model. Ultimately, ATF3 was found to promote miR-21-3p transcription in IFN-γ-driven ferroptosis.ConclusionsMiR-21–3 p upregulation contributes to IFN-γ-driven ferroptosis and synergizes with anti-PD-1 antibody. Nanoparticle delivery of miR-21–3 p is a promising therapeutic approach to increase immunotherapy efficacy without obvious systemic side effects.

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“…In Figure , a therapeutic siRNA (Section 3.2) is delivered to target cells involving a specific miRNA. [ 169 ] In the steps I, II, and III, backbone‐rigidified Y‐shaped triangular DNA bricks were prepared, and tiled onto a gold nanoparticle packaged with a siRNA (red). As the result, 3D core–shell nanoarchitecture was formed.…”

Section: Smart Dds Using Intracellular Signals As Stimuli To Accompli...mentioning

confidence: 99%

Section: Smart Dds Using Intracellular Signals As Stimuli To Accompli...mentioning

confidence: 99%

DNA‐Based Nanoarchitectures as Eminent Vehicles for Smart Drug Delivery Systems

Komiyama

Shigi

Ariga

2022

Adv Funct Materials

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In order to cure diseases efficiently with minimal side effects in sophisticated medicine, eminent drugs must be selectively delivered to diseased parts and allow to work only there. However, most of drug delivery systems (DDSs) previously proposed are not yet sufficiently selective and effective. This review covers recent developments of DDS in which DNA nanoarchitectures are employed as drug carriers. From short DNA fragments, a variety of complicated nanomedicines are fabricated to show unprecedentedly smart DDS functions. Encapsulated drugs are released mostly through controlled disassembly of DNA nanoarchitectures. Recent attention has been focusing to the use of appropriate stimuli to regulate each process in the DDS (delivery of drug, its release, and others) for further improved therapy. As intracellular stimuli for the regulation, various endogenous compounds (e.g., mRNA and enzymes), which are specifically abundant in target cells, are employed. Alternatively, physical perturbation (e.g., light irradiation) is provided from outside of tissues to control DDS. By combining multiple strategies in terms of new concepts, enormously smart DDSs are being achieved. Further progresses of these approaches in the future are guaranteed by complete freedom of molecular design in DNA nanoarchitectonics.

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Programmably tiling rigidified DNA brick on gold nanoparticle as multi-functional shell for cancer-targeted delivery of siRNAs

Cited by 72 publications

References 64 publications

Self-Protected DNAzyme Walker with a Circular Bulging DNA Shield for Amplified Imaging of miRNAs in Living Cells and Mice

Self-Protected DNAzyme Walker with a Circular Bulging DNA Shield for Amplified Imaging of miRNAs in Living Cells and Mice

Nanoparticle delivery of miR-21-3p sensitizes melanoma to anti-PD-1 immunotherapy by promoting ferroptosis

DNA‐Based Nanoarchitectures as Eminent Vehicles for Smart Drug Delivery Systems

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