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      An orthogonally regulatable DNA nanodevice for spatiotemporally controlled biorecognition and tumor treatment

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          Abstract

          Orthogonal near-infrared light–controlled DNA nanodevices allow for biorecognition and treatment at right time and place.

          Abstract

          Despite the potential of nanodevices for intelligent drug delivery, it remains challenging to develop controllable therapeutic devices with high spatial-temporal selectivity. Here, we report a DNA nanodevice that can achieve tumor recognition and treatment with improved spatiotemporal precision under the regulation of orthogonal near-infrared (NIR) light. The nanodevice is built by combining an ultraviolet (UV) light–activatable aptamer module and a photosensitizer (PS) with up-conversion nanoparticle (UCNP) that enables the operation of the nanodevice with deep tissue–penetrable NIR light. The UCNPs can convert two distinct NIR excitations into orthogonal UV and green emissions for programmable photoactivation of the aptamer modules and PSs, respectively, allowing spatiotemporally controlled target recognition and photodynamic antitumor effect. Furthermore, when combined with immune checkpoint blockade therapy, the nanodevice results in regression of untreated distant tumors. This work provides a new approach for regulation of diagnostic and therapeutic activity at the right time and place.

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          Most cited references35

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          Upconversion and anti-Stokes processes with f and d ions in solids.

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            Aptamers as therapeutics

            Key Points Aptamers are single-stranded oligonucleotides that fold into defined architectures and bind to targets such as proteins. In binding proteins they often inhibit protein–protein interactions and thereby may elicit therapeutic effects such as antagonism. Aptamers are discovered using SELEX (systematic evolution of ligands by exponential enrichment), a directed in vitro evolution technique in which large libraries of degenerate oligonucleotides are iteratively and alternately partitioned for target binding. They are then amplified enzymatically until functional sequences are identified by the sequencing of cloned individuals. For most therapeutic purposes, aptamers are truncated to reduce synthesis costs, modified at the sugars and capped at their termini to increase nuclease resistance, and conjugated to polyethylene glycol or another entity to reduce renal filtration rates. The first aptamer approved for a therapeutic application was pegaptanib sodium (Macugen; Pfizer/Eyetech), which was approved in 2004 by the US Food and Drug Administration for macular degeneration. Eight other aptamers are currently undergoing clinical evaluation for various haematology, oncology, ocular and inflammatory indications. Aptamers are ultimately chemically synthesized in a readily scalable process in which specific conjugation points are introduced with defined stereochemistry. Unlike some protein therapeutics, aptamers do not elicit antibodies, and because aptamers generally contain sugars modified at their 2′-positions, Toll-like receptor-mediated innate immune responses are also abrogated. As aptamers are oligonucleotides they can be readily assembled into supramolecular multi-component structures using hybridization. Owing to the fact that binding to appropriate cell-surface targets can lead to internalization, aptamers can also be used to deliver therapeutic cargoes such as small interfering RNA. Supramolecular assemblies of aptamers and delivery agents have already been demonstrated in vivo and may pave the way for further therapeutic strategies with this modality in the future.
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              A logic-gated nanorobot for targeted transport of molecular payloads.

              We describe an autonomous DNA nanorobot capable of transporting molecular payloads to cells, sensing cell surface inputs for conditional, triggered activation, and reconfiguring its structure for payload delivery. The device can be loaded with a variety of materials in a highly organized fashion and is controlled by an aptamer-encoded logic gate, enabling it to respond to a wide array of cues. We implemented several different logical AND gates and demonstrate their efficacy in selective regulation of nanorobot function. As a proof of principle, nanorobots loaded with combinations of antibody fragments were used in two different types of cell-signaling stimulation in tissue culture. Our prototype could inspire new designs with different selectivities and biologically active payloads for cell-targeting tasks.
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                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                June 2020
                17 June 2020
                : 6
                : 25
                : eaba9381
                Affiliations
                [1 ]CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China.
                [2 ]College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing 100049, China.
                [3 ]CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.
                [4 ]GBA Research Innovation Institute for Nanotechnology, Guangdong 510700, China.
                Author notes
                [*]

                These authors contributed equally to this work.

                []Corresponding author. Email: zhaoyl@ 123456nanoctr.cn (Y.Z.); lilele@ 123456nanoctr.cn (L.L.)
                Author information
                http://orcid.org/0000-0002-9207-8838
                http://orcid.org/0000-0002-4906-3809
                http://orcid.org/0000-0002-7274-5402
                http://orcid.org/0000-0002-9586-9360
                http://orcid.org/0000-0001-8593-9292
                Article
                aba9381
                10.1126/sciadv.aba9381
                7299621
                32596474
                e90ffb04-530c-4b3f-9ea0-7eacef8e6281
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 17 January 2020
                : 04 May 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 21822401
                Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 21771044
                Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 21805060
                Categories
                Research Article
                Research Articles
                SciAdv r-articles
                Engineering
                Materials Science
                Applied Sciences and Engineering
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