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Lingling Shan,1 Yudie Li,1 Yifan Ma,2 Yang Yang,1 Jing Wang,1 Lei Peng,1 Weiwei Wang,1 Fang Zhao,1 Wanrong Li,1 Xiaoyuan Chen3– 6 1Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China; 2Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 3Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore; 4Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 5Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 6Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore, SingaporeCorrespondence: Xiaoyuan Chen; Lingling Shan, Email chen.shawn@nus.edu.sg; ntlinger-300@163.comBackground: While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still an essential problem.Methods: We exploited nanoparticle coordination between ferric (Fe2+) ions and telomerase-targeting hairpin DNA structures to encapsulate doxorubicin (DOX) and fabricated Fe2+-DNA@DOX nanoparticles (BDDF NPs). This work studied the NIR fluorescence imaging and pharmacokinetic studies targeting the ability and biodistribution of BDDF NPs. In vitro and vivo studies investigated the nano formula’s toxicity, imaging, and synergistic therapeutic effects.Results: The enhanced permeability and retention (EPR) effect and tumor targeting resulted in prolonged blood circulation times and high tumor accumulation. Significantly, BDDF NPs could reduce DOX-mediated cardiac toxicity by improving the antioxidation ability of cardiomyocytes based on the different telomerase activities and iron dependency in normal and tumor cells. The synergistic treatment efficacy is enhanced through Fe2+-mediated ferroptosis and the β-catenin/p53 pathway and improved the tumor inhibition rate.Conclusion: Harpin DNA-based nanoplatforms demonstrated prolonged blood circulation, tumor drug accumulation via telomerase-targeting, and synergistic therapy to improve antitumor drug efficacy. Our work sheds new light on nanomaterials for future synergistic chemotherapy. Keywords: DNA nanomaterials, targeting, imaging, synergistic therapy

Yu-Chi Tu,* Yu-Mei Wang,* Li-Jun Yao Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-Jun Yao, Email ljyao@hust.edu.cnAbstract: DNA can be used for precise construction of complex and flexible micro-nanostructures, including DNA origami, frame nucleic acids, and DNA hydrogels. DNA nanomaterials have good biocompatibility and can enter macrophages via scavenger receptor-mediated endocytosis. DNA nanomaterials can be uniquely and flexibly designed to ensure efficient uptake by macrophages, which represents a novel strategy to regulate macrophage function. With the development of nanotechnology, major advances have been made in the design and manufacturing of DNA nanomaterials for clinical therapy. In diseases accompanied by macrophage disturbances including tumor, infectious diseases, arthritis, fibrosis, acute lung injury, and atherosclerosis, DNA nanomaterials received considerable attention as potential treatments. However, we lack sufficient information to guarantee precise targeting of macrophages by DNA nanomaterials, which precludes their therapeutic applications. In this review, we summarize recent studies of macrophage-targeting DNA nanomaterials and discuss the limitations and challenges of this approach with regard to its potential use as a biological therapy.Keywords: macrophages, DNA nanomaterials, therapy, macrophage-related diseases

Abstract Wounds are one of the most common health issues, and the cost of wound care and healing has continued to increase over the past decade. In recent years, there has been growing interest in developing innovative strategies to enhance the efficacy of wound healing. Tetrahedral framework nucleic acids (tFNAs) have emerged as a promising tool for wound healing applications due to their unique structural and functional properties. Therefore, it is of great significance to summarize the applications of tFNAs for wound healing. This review article provides a comprehensive overview of the potential of tFNAs as a novel therapeutic approach for wound healing. In this review, we discuss the possible mechanisms of tFNAs in wound healing and highlight the role of tFNAs in modulating key processes involved in wound healing, such as cell proliferation and migration, angiogenesis, and tissue regeneration. The targeted delivery and controlled release capabilities of tFNAs offer advantages in terms of localized and sustained delivery of therapeutic agents to the wound site. In addition, the latest research progress on tFNAs in wound healing is systematically introduced. We also discuss the biocompatibility and biosafety of tFNAs, along with their potential applications and future directions for research. Finally, the current challenges and prospects of tFNAs are briefly discussed to promote wider applications.

DNA nanomaterials have been widely employed for various biomedical applications. With rapid development of chemical modification of nucleic acid, serials of stimuli‐responsive elements are included in the multifunctional DNA nanomaterials. In this review, we summarize the recent advances in light responsive DNA nanomaterials based on photocleavage/photodecage, photoisomerization, and photocrosslinking for efficient bioimaging (including imaging of small molecule, microRNA, and protein) and drug delivery (including delivery of small molecule, nucleic acid, and gene editing system). We also discuss the remaining challenges and future perspectives of the light responsive DNA nanomaterials in biomedical applications. [ABSTRACT FROM AUTHOR]

Hydrocephalus is one of the most common brain disorders and a life‐long incurable condition. An empirical "one‐size‐fits‐all" approach of cerebrospinal fluid (CSF) shunting remains the mainstay of hydrocephalus treatment and effective pharmacotherapy options are currently lacking. Macrophage‐mediated ChP inflammation and CSF hypersecretion have recently been identified as a significant discovery in the pathogenesis of hydrocephalus. In this study, a pioneering DNA nano‐drug (TSOs) is developed by modifying S2 ssDNA and S4 ssDNA with SPAK ASO and OSR1 ASO in tetrahedral framework nucleic acids (tFNAs) and synthesis via a one‐pot annealing procedure. This construct can significantly knockdown the expression of SPAK and OSR1, along with their downstream ion channel proteins in ChP epithelial cells, thereby leading to a decrease in CSF secretion. Moreover, these findings indicate that TSOs effectively inhibit the M0 to M1 phenotypic switch of ChP macrophages via the MAPK pathways, thus mitigating the cytokine storm. In in vivo post‐hemorrhagic hydrocephalus (PHH) models, TSOs significantly reduce CSF secretion rates, alleviate ChP inflammation, and prevent the onset of hydrocephalus. These compelling results highlight the potential of TSOs as a promising therapeutic option for managing hydrocephalus, with significant applications in the future. [ABSTRACT FROM AUTHOR]

Wounds are one of the most common health issues, and the cost of wound care and healing has continued to increase over the past decade. In recent years, there has been growing interest in developing innovative strategies to enhance the efficacy of wound healing. Tetrahedral framework nucleic acids (tFNAs) have emerged as a promising tool for wound healing applications due to their unique structural and functional properties. Therefore, it is of great significance to summarize the applications of tFNAs for wound healing. This review article provides a comprehensive overview of the potential of tFNAs as a novel therapeutic approach for wound healing. In this review, we discuss the possible mechanisms of tFNAs in wound healing and highlight the role of tFNAs in modulating key processes involved in wound healing, such as cell proliferation and migration, angiogenesis, and tissue regeneration. The targeted delivery and controlled release capabilities of tFNAs offer advantages in terms of localized and sustained delivery of therapeutic agents to the wound site. In addition, the latest research progress on tFNAs in wound healing is systematically introduced. We also discuss the biocompatibility and biosafety of tFNAs, along with their potential applications and future directions for research. Finally, the current challenges and prospects of tFNAs are briefly discussed to promote wider applications. [ABSTRACT FROM AUTHOR]

As an important barrier between the cytoplasm and the microenvironment of the cell, the cell membrane is essential for the maintenance of normal cellular physiological activities. An abnormal cell membrane is a crucial symbol of body dysfunction and the occurrence of variant diseases; therefore, the visualization and monitoring of biomolecules associated with cell membranes and disease markers are of utmost importance in revealing the biological functions of cell membranes. Due to their biocompatibility, programmability, and modifiability, DNA nanomaterials have become increasingly popular in cell fluorescence imaging in recent years. In addition, DNA nanomaterials can be combined with the cell membrane in a specific manner to enable the real-time imaging of signal molecules on the cell membrane, allowing for the real-time monitoring of disease occurrence and progression. This article examines the recent application of DNA nanomaterials for fluorescence imaging on cell membranes. First, we present the conditions for imaging DNA nanomaterials in the cell membrane microenvironment, such as the ATP, pH, etc. Second, we summarize the imaging applications of cell membrane receptors and other molecules. Finally, some difficulties and challenges associated with DNA nanomaterials in the imaging of cell membranes are presented. [ABSTRACT FROM AUTHOR]

Abstract DNA nanoparticles hold great promise for a range of biological applications, including the development of cutting-edge treatments and diagnostic tests. Their subnanometer-level addressability enables precise, specific modifications with a variety of chemical and biological entities, making them ideal as diagnostic instruments and carriers for targeted delivery. This paper focuses on the potential of DNA nanomaterials, which offer scalability, programmability, and functionality. For example, they can be engineered to provide highly specific biosensing and bioimaging capabilities and show promise as a platform for disease diagnosis and treatment. Successful operation of various biomedical nanomaterials has been demonstrated both in vitro and in vivo. However, there are still significant challenges to overcome, including the need to improve the scalability and reliability of the technology, and to ensure safety in clinical applications. We discuss these challenges and opportunities in detail and highlight the progress and prospects of DNA nanotechnology for biomedical applications.

The clustered regularly interspaced short palindromic repeats (CRISPR)/associated protein (CRISPR/Cas) system has been exploited as an efficient gene editing tool with precise site specificity and high efficiency; the delivery of the CRISPR/Cas system is critical for the efficacy of therapeutics and remains challenging. DNA nanomaterials are widely utilized as promising delivery carriers for gene agents because of their excellent molecular recognition capabilities, sequence programmability, and biocompatibility. Herein, recent advances in DNA nanomaterials for the delivery of CRISPR/Cas systems are summarized. Based on their construction strategy, DNA nanomaterial‐based carriers are categorized as branched DNA‐based nanostructures or rolling circle amplification (RCA)‐based DNA nanostructures. Representative studies on the design of DNA nanomaterials as CRISPR/Cas system delivery carriers are highlighted. The current challenges and opportunities for the development of DNA nanomaterials for the delivery of CRISPR/Cas systems are also discussed. It is envisioned that with the development of DNA nanotechnology, DNA nanomaterials will open up new possibilities for CRISPR/Cas‐based therapeutics. [ABSTRACT FROM AUTHOR]

DNA nanoparticles hold great promise for a range of biological applications, including the development of cutting-edge treatments and diagnostic tests. Their subnanometer-level addressability enables precise, specific modifications with a variety of chemical and biological entities, making them ideal as diagnostic instruments and carriers for targeted delivery. This paper focuses on the potential of DNA nanomaterials, which offer scalability, programmability, and functionality. For example, they can be engineered to provide highly specific biosensing and bioimaging capabilities and show promise as a platform for disease diagnosis and treatment. Successful operation of various biomedical nanomaterials has been demonstrated both in vitro and in vivo. However, there are still significant challenges to overcome, including the need to improve the scalability and reliability of the technology, and to ensure safety in clinical applications. We discuss these challenges and opportunities in detail and highlight the progress and prospects of DNA nanotechnology for biomedical applications. [ABSTRACT FROM AUTHOR]

The past few decades have witnessed the evolving paradigm for cancer therapy from nonspecific cytotoxic agents to selective, mechanism‐based therapeutics, especially immunotherapy. In particular, the integration of nanomaterials with immunotherapy is proven to improve the therapeutic outcome and minimize off‐target toxicity in the treatment. As a novel nanomaterial, DNA‐based self‐assemblies featuring uniform geometries, feasible modifications, programmability, surface addressability, versatility, and intrinsic biocompatibility, are extensively exploited for innovative and effective cancer immunotherapy. In this review, the successful employment of DNA nanoplatforms for cancer immunotherapy, including the delivery of immunogenic cell death inducers, adjuvants and vaccines, immune checkpoint blockers as well as the application in immune cell engineering and adoptive cell therapy is summarized. The remaining challenges and future perspectives regarding the pharmacokinetics/pharmacodynamics, in vivo fate and immunogenicity of DNA materials, and the design of intelligent DNA nanomedicine for individualized cancer immunotherapy are also discussed. [ABSTRACT FROM AUTHOR]

Food safety has always been a major global challenge to human health and the effective detection of harmful substances in food can reduce the risk to human health. However, the food industry has been plagued by a lack of effective and sensitive safety monitoring methods due to the tension between the cost and effectiveness of monitoring. DNA-based hydrogels combine the advantages of biocompatibility, programmability, the molecular recognition of DNA molecules, and the hydrophilicity of hydrogels, making them a hotspot in the research field of new nanomaterials. The stimulus response property greatly broadens the function and application range of DNA hydrogel. In recent years, DNA hydrogels based on stimulus-responsive mechanisms have been widely applied in the field of biosensing for the detection of a variety of target substances, including various food contaminants. In this review, we describe the recent advances in the preparation of stimuli-responsive DNA hydrogels, highlighting the progress of its application in food safety detection. Finally, we also discuss the challenges and future application of stimulus-responsive DNA hydrogels. [ABSTRACT FROM AUTHOR]

DNA three-way junctions are critical in various biological processes and hold significant potential for disease treatment and therapeutic applications. In this study, it is demonstrated that triple-stranded dinuclear [Ni 2 L 3 ] 4+ cylinders (L = C 25 H 20 N 4 ) exhibit a preferential binding affinity for Y-shaped DNA three-way junctions (3WJs), even in the presence of an excess of competing DNA structures, including G-quadruplexes. Notably, the investigated Ni(II) cylinders are capable of halting DNA synthesis catalyzed by DNA polymerase by stabilizing the 3WJ on the template strand. Using an extended 1D nanoarchitecture model, it is further established the high affinity and selectivity of the cylinders for DNA 3WJs and explored their potential application in stabilizing short-armed 3WJs for constructing DNA nanomaterials. The combined use of Ni(II) cylinders and DNA damage response inhibitors also revealed that the cylinders promote DNA damage, leading to the formation of double-strand breaks. This effect is likely associated with i) the binding of cylinders to 3WJs and ii) the cytotoxic activity of the cylinders in cancer cells., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

The nanofibers assembled from the host–guest complex of cyclodextrin and porphyrin-DNA amphiphiles, could anchored with AS1411/Hemin through DNA hybridization. The host–guest interaction of cyclodextrin and porphyrin inhibited the π-π stacking of porphyrin molecules. Meantime, the introduced AS1411/Hemin could not only targeted recognize cancer cells but also catalyze H 2 O 2 to generate O 2 , thus promoting the porphyrin-based photodynamic therapy. [Display omitted] • TPP-D18/β-CD amphiphiles self-assemble into nanofibers in TM buffer and remain nanofibers after hybridizing with AS1411/Hemin. • AS1411 at the surface of the nanofiber enables to specifically target HeLa cells. • AS1411/Hemin complex catalyzes H 2 O 2 to generate O 2 in tumor cells, alleviating hypoxia and enhancing the efficacy of PDT. • It provides a simple strategy to construct the programmable multifunctional nanocarrier for enhanced and targeted photodynamic therapy. Targeted photodynamic therapy is considered superior to conventional photodynamic therapy due to the enhanced uptake of photosensitizers by tumor cells. However, porphyrin-based photodynamic therapy is still limited due to the low hydrophilicity, poor biocompatibility and susceptibility to quenching of photosensitizers. Herein, we report cyclodextrin-activated porphyrin-DNA nanofibers with AS1411/Hemin toeholds, which enable targeted cancer cells recognition and catalytic oxygenation for enhanced photodynamic therapy. The nanofibers are formed through the self-assembly of the host–guest complex of cyclodextrin and porphyrin-DNA amphiphiles, and can be further functionalized on the surface with AS1411/Hemin. AS1411/Hemin can specifically target nucleolin-overexpressing cancer cells and catalyze conversion of excessive H 2 O 2 into O 2 within tumor cells, thereby alleviating tumor hypoxia and further cascaded enhancing PDT efficacy. These results suggest that the programmable and multifunctional nanofiber provided an effective nanoplatform for enhanced and targeted photodynamic therapy. [ABSTRACT FROM AUTHOR]

Synthesis and anti-angiogenic efficacy of tFNA@AF. Excessive angiogenesis is stimulated by the unbalance between pro-angiogenic and anti-angiogenic factors under pathological circumstances. The tFNA@AF could effectively block the interaction between vascular endothelial growth factor receptor 1 (VEGFR1) and its ligands, resulting in the inactivation of downstream PI3K/AKT/m-TOR signaling pathway. Regulating uncontrolled angiogenesis, the tFNA@AF shows exciting application potential in tumor progression and cornea injury. [Display omitted] • Low solubility, instability limit the application of anti-Flt 1 peptide. • tFNA provides an effective and safe strategy for AF delivery. • AF-functionalized DNA tetrahedron showed enhanced inhibitory effect on angiogenesis. Angiogenesis is an important and necessary process in tissue regeneration and recovery, but suppressing such process is also a critical therapeutic consideration in some diseases including tumor and corneal neovascularization. Currently, pathological angiogenesis is mainly inhibited through the blockade of the interaction between vascular endothelial growth factor receptor (VEGFR) and its ligands. Compared to traditional anti-angiogenic agents such as monoclonal antibody and tyrosine kinase inhibitor, polypeptide has gained growing interests for high unit activity, few adverse reactions, and low costs. Among them, anti-Flt1 (AF) peptide could inhibit VEGFR1-induced endothelial cell migration and tube formation, showing excellent anti-angiogenic activity. Addressing the issues of low water solubility, instability, and poor bioavailability would significantly hinder the applications of AF. Herein, we prepared an AF functionalized tetrahedral framework nucleic acid (tFNA@AF) to overcome the abovementioned limitations of AF. The tFNA@AF presented enhanced structural stability and cellular uptake of AF, and exhibited superior bioavailability and satisfying anti-angiogenic effectiveness in vitro. Furthermore, tFNA@AF also demonstrated high-efficiency pathological angiogenesis inhibition on tumor-bearing mice of triple-negative breast cancer and corneal neovascularization of cornea cauterized rats, two typical models of tumor and traumatic cornea where angiogenesis is not anticipant. Our tFNA@AF as a novel polypeptide-nucleic acid conjugated nanomaterials showed superior bioavailability and high anti-angiogenic effectiveness, suggesting that with incremental improvements the nanomedicine may offer potentially useful treatment aid for anti-angiogenic therapy to prevent tumor growth and corneal neovascularization. [ABSTRACT FROM AUTHOR]

The synchronous detection and regulation of microRNAs (miRNAs) are essential for the early tumor diagnosis and treatment but remains a challenge. An integrative DNA tetrahedral nanomachine was self-assembled for sensitive detection and negative feedback regulation of intracellular miRNAs. This nanomachine comprised a DNA tetrahedron nanostructure as the framework, and a miRNA inhibitor-controlled allosteric DNAzyme as the core. The DNA tetrahedron brought the DNAzyme and the substrate in spatial proximity and facilitated the cellular uptake of DNAzyme. In allosteric regulation of DNAzyme, the locked tetrahedral DNAzyme (L-tetra-D) and active tetrahedral DNAzyme (A-Tetra-D) were controlled by miRNA inhibitor. The combination of miRNA inhibitor and target could trigger the conformational change from L-tetra-D to A-Tetra-D. A-Tetra-D cleaved the substrate and released fluorescence for intracellular miRNA biosensing. The DNA tetrahedral nanomachine showed excellent sensitivity (with detection limit down to 0.77 pM), specificity (with one-base mismatch discrimination), biocompatibility and stability. Simultaneously, miRNA stimulus-unlocked inhibitor introduced by our nanomachine exhibited the synchronous regulation of target cells, of which regulatory performance has been verified by the upregulated levels of downstream genes/proteins and the increased cellular apoptosis. Our study demonstrated that the DNA tetrahedral nanomachine is a promising biosense-and-treat tool for the synchronous detection and regulation of intracellular miRNA, and is expected to be applied in the early diagnosis and tailored management of cancers.

Sensitive and quantitative detection of chemical and biological molecules for screening, diagnosis and monitoring diseases is essential to treatment planning and response monitoring. Electrochemical biosensors are fast, sensitive, and easy to miniaturize, which has led to rapid development in clinical diagnosis. Benefiting from their excellent molecular recognition ability and high programmability, DNA nanomaterials could overcome the Debye length of electrochemical biosensors by simple molecular design and are well suited as recognition elements for electrochemical biosensors. Therefore, to enhance the sensitivity and specificity of electrochemical biosensors, significant progress has been made in recent years by optimizing the DNA nanomaterials design. Here, the establishment of electrochemical sensing strategies based on DNA nanomaterials is reviewed in detail. First, the structural design of DNA nanomaterial is examined to enhance the sensitivity of electrochemical biosensors by improving recognition and overcoming Debye length. In addition, the strategies of electrical signal transduction and signal amplification based on DNA nanomaterials are reviewed, and the applications of DNA nanomaterial-based electrochemical biosensors and integrated devices in clinical diagnosis are further summarized. Finally, the main opportunities and challenges of DNA nanomaterial-based electrochemical biosensors in detecting disease biomarkers are presented in an aim to guide the design of DNA nanomaterial-based electrochemical devices with high sensitivity and specificity.

Extracellular vesicles (EVs) are cell-secreted biological nanoparticles that are critical mediators of intercellular communication. They contain diverse bioactive components, which are promising diagnostic biomarkers and therapeutic agents. Their nanosized membrane-bound structures and innate ability to transport functional cargo across major biological barriers make them promising candidates as drug delivery vehicles. However, the complex biology and heterogeneity of EVs pose significant challenges for their controlled and actionable applications in diagnostics and therapeutics. Recently, DNA molecules with high biocompatibility emerge as excellent functional blocks for surface engineering of EVs. The robust Watson-Crick base pairing of DNA molecules and the resulting programmable DNA nanomaterials provide the EV surface with precise structural customization and adjustable physical and chemical properties, creating unprecedented opportunities for EV biomedical applications. This review focuses on the recent advances in the utilization of programmable DNA to engineer EV surfaces. The biology, function, and biomedical applications of EVs are summarized and the state-of-the-art achievements in EV isolation, analysis, and delivery based on DNA nanomaterials are introduced. Finally, the challenges and new frontiers in EV engineering are discussed., (© 2023 Wiley‐VCH GmbH.)

Deoxyribonucleic acid (DNA) has been an emerging building block to construct functional biomaterials. Due to their programmable sequences and rich responsiveness, DNA has attracted rising attention in the construction of intelligent nanomaterials with predicable nanostructure and adjustable functions, which has shown great potential in drug delivery. On the one hand, the DNA sequences with molecule recognition, responsiveness, and therapeutic efficacy can be easily integrated to the framework of DNA nanomaterials by sequence designing; on the other hand, the rich chemical groups on DNA molecules provide binding points for other functional units. In this review, we divided the functionalization modules in the construction of DNA nanomaterials into three types, including targeting modules, responsive modules, and therapeutic modules. Based on these modules, five DNA kinds of representative nanomaterials applied in drug delivery were introduced, including DNA nanogel, DNA origami, DNA framework, DNA nanoflower, and DNA hybrid nanosphere. Finally, we discussed the challenges in the transition of DNA materials to clinical applications. We expect that this review can help readers to obtain a deeper understanding of DNA materials, and further promote the development of these intelligent materials to real world's application. This article is categorized under:Biology‐Inspired Nanomaterials > Nucleic Acid‐Based StructuresNanotechnology Approaches to Biology > Nanoscale Systems in Biology [ABSTRACT FROM AUTHOR]

Food safety has always been a major global challenge to human health and the effective detection of harmful substances in food can reduce the risk to human health. However, the food industry has been plagued by a lack of effective and sensitive safety monitoring methods due to the tension between the cost and effectiveness of monitoring. DNA-based hydrogels combine the advantages of biocompatibility, programmability, the molecular recognition of DNA molecules, and the hydrophilicity of hydrogels, making them a hotspot in the research field of new nanomaterials. The stimulus response property greatly broadens the function and application range of DNA hydrogel. In recent years, DNA hydrogels based on stimulus-responsive mechanisms have been widely applied in the field of biosensing for the detection of a variety of target substances, including various food contaminants. In this review, we describe the recent advances in the preparation of stimuli-responsive DNA hydrogels, highlighting the progress of its application in food safety detection. Finally, we also discuss the challenges and future application of stimulus-responsive DNA hydrogels.

Tetrahedral framework nucleic acid (tFNA), a special DNA nanodevice, is widely applied in diverse biomedical fields. Due to its high programmability, biocompatibility, tissue permeability as well as its capacity for cell proliferation and differentiation, tFNA presents a powerful tool that could overcome potential barriers in the treatment of neurological disorders. This review evaluates recent studies on the use and progress of tFNA-based nanomaterials in neurological disorders.

Implementation of adjuvants is a requirement for inducing antigen-specific immune responses against infectious diseases. The conventional aluminum adjuvants used in clinical trials suffer from insufficient cellular immune response. Herein, we develop a bi-adjuvant nanovaccine containing receptor-binding domain (RBD) as antigen and DNA programmed Mg/Al layered double hydroxide (Mg/Al-LDH) as adjuvants, and thus achieve co-activation of potent humoral and cellular immune responses. The Mg/Al-LDH consisting of positively charged layers is firstly employed as scaffold to adsorb antigen via electrostatic interaction, and then CpG and dendritic cell (DC)-targeting aptamers co-encoded ultra-long DNA chains are easily decorated on the Mg/Al-LDH via interfacial assembly. The nanoscale formulations and interfacial targeting aptamers of nanovaccine facilitate their endocytosis by DC cells; the Mg/Al-LDH structure is acid-responsive and ensures the Al ions-inducing antigen cross-presentation for durable generation of antibody (Th2 immune response); and the agonist CpG in DNA chains can bind to the Toll-like receptor 9 (TLR 9) to activate cellular immunity (Th1 immune response). The bi-adjuvant nanovaccine fully combines the advantages of nanosheet alum-like adjuvant and precisely customization of DNA, and thus balances the Th1/Th2 immune response for compensating the deficiency of traditional alum adjuvant, providing a design guidance for creating next-generation of safe and efficient adjuvants in immunology. [Display omitted] • The nanovaccine was constructed using LDH as a scaffold which adsorbed DNA chains and RBD antigens byinterfacial assembly. • The DNA-LDH facilitated the endocytosis and cross presentation of RBD antigens. • The DNA-LDH achieved co-activation of potent humoral and cellular immune responses. • The DNA-LDH balanced the Th1/Th2 immune response which compensated the deficiency of traditional alum adjuvant. [ABSTRACT FROM AUTHOR]

Nucleic acid-based drugs exhibited great potential in cancer therapeutics. However, the biological instability of nucleic acid-based drugs seriously hampered their clinical applications. Efficient in vivo delivery is the key to the clinical application of nucleic acid-based drugs. As a natural biological macromolecule, DNA has unique properties, such as excellent biocompatibility, molecular programmability, and precise assembly controllability. With the development of DNA nanotechnology, DNA nanomaterials have demonstrated significant advantages as delivery vectors of nucleic acid-based drugs by virtue of the inherent nucleic acid properties. In this study, the recent progress in the design of DNA-based nanomaterials for nucleic acid delivery is summarized. The DNA nanomaterials are categorized according to the components including pure DNA nanomaterials, DNA-inorganic hybrid nanomaterials, and DNA-organic hybrid nanomaterials. Representative applications of DNA nanomaterials in the controlled delivery of nucleic acid-based drugs are exemplified to show how DNA nanomaterials are rationally and exquisitely designed to address application issues in cancer therapy. At the end of this study, the challenges and future development of DNA nanomaterials are discussed.

There has been a constant and urgent need to upgrade the current diagnostic technologies to the next generation by utilizing innovative advanced technologies in order to meet new challenges. Micro/nano technology, a series of methods for design and manipulation materials at the micrometer and nanometer scales, which perfectly covers the key building blocks of life including cells, organelles, proteins, nucleic acids, and other components, has unique advantages over current diagnostic methods. For the applications of micro–nano technology in next‐generation diagnostics, three categories, including microchip‐based devices, DNA nanomachines, and DNA nanomaterials, are extensively reviewed. Specifically, for the microchip‐based devices, terahertz technology and surface acoustic wave technology show their ultrasensitivity of label‐free, amplification‐free diagnosis. For the DNA nanomachines, DNA tweezers, DNA robots, and DNA walkers exhibit a great potential for diagnosis with the arbitrary structures and controllable motion behaviors. For the DNA nanomaterials, DNA aptamers, DNAzymes, and hybrid DNA nanomaterials provide sensitive biorecognition elements and versatile signal transductions, which are demonstrated as promising material candidates for the next‐generation diagnostics. Through this review, it is envisioned that micro/nano technologies will play an important role in the next‐generation diagnostics. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are cell-derived nanovesicles comprising a myriad of molecular cargo such as proteins and nucleic acids, playing essential roles in intercellular communication and physiological and pathological processes. EVs have received substantial attention as noninvasive biomarkers for disease diagnosis and prognosis. Owing to their ability to recognize protein and nucleic acid targets, DNA-based nanomaterials with excellent programmability and modifiability provide a promising tool for the sensitive and accurate detection of molecular cargo carried by EVs. In this perspective, recent advancements in EV analysis using a variety of DNA-based nanomaterials are summarized, which can be broadly classified into three categories: linear DNA probes, DNA nanostructures, and hybrid DNA nanomaterials. The design, construction, advantages, and disadvantages of different types of DNA nanomaterials, as well as their performance for detecting EVs are reviewed. The challenges and opportunities in the field of EV analysis by DNA nanomaterials are also discussed., (© 2023 Wiley‐VCH GmbH.)

Oligonucleotides are biopolymers that can be easily modified at various locations. Thereby, the attachment of metal complexes to nucleic acid derivatives has emerged as a common pathway to improve the understanding of biological processes or to steer oligonucleotides towards novel applications such as electron transfer or the construction of nanomaterials. Among the different metal complexes coupled to oligonucleotides, ruthenium complexes, have been extensively studied due to their remarkable properties. The resulting DNA-ruthenium bioconjugates have already demonstrated their potency in numerous applications. Consequently, this review focuses on the recent synthetic methods developed for the preparation of ruthenium complexes covalently linked to oligonucleotides. In addition, the usefulness of such conjugates will be highlighted and their applications from nanotechnologies to therapeutic purposes will be discussed. [ABSTRACT FROM AUTHOR]

Exosomes are membrane-bound nanovesicles secreted by all cell types and contain diverse molecules. Detecting cancer-derived exosomes and their cargo, which are closely related to cancer staging, has significant clinical potential for early cancer diagnosis and prognosis prediction. Benefiting from the unique physical and chemical properties of DNA nanomaterials, DNA nanomaterial-based biosensors provide potential platforms for clinically accurate analysis of exosomes. This review highlights the advances, challenges, and outlook on DNA nanomaterial-based biosensors for cancer-derived exosomes and their cargo detection. Two-dimensional and three-dimensional DNA nanomaterials, including molecular beacons, DNAzymes, branched DNA, DNA nanowires, G-quadruplexes, DNA tetrahedron, DNA nanoflowers, DNA hydrogels, DNA cubes, and the state-of-the-art developments in exosomes and their cargo detection are elaborated in detail. Finally, the current gap in clinical applications of DNA nanomaterial-based biosensing technologies is discussed, which could offer guidance for the future application of these technologies in precise analysis of exosomes and early diagnosis of cancer. • Overview of the application of DNA nanomaterials in exosomes and their cargo detection. • DNA nanomaterials-based biosensors present high specificity, sensitivity, multiplex detection capability and programmability. • Strategies for enhancing the clinical exosome analysis application of DNA nanomaterials-based biosensors are fully discussed. • The application challenges and prospects were summarized. [ABSTRACT FROM AUTHOR]

G-quadruplexes (G4s) and i-motifs (iMs) are tetraplex DNA structures. Sequences capable of forming G4/iMs are abundant near the transcription start sites (TSS) of several genes. G4/iMs affect gene expression in vitro. Depending on the gene, the presence of G4/iMs can enhance or suppress expression, making it challenging to discern the underlying mechanism by which they operate. Factors affecting G4/iM structures can provide additional insight into their mechanism of regulation. One such factor is epigenetic modification. The 5-hydroxymethylated cytosines (5hmCs) are epigenetic modifications that occur abundantly in human embryonic stem cells (hESC). The 5hmCs, like G4/iMs, are known to participate in gene regulation and are also enriched near the TSS. We investigated genomic co-localization to assess the possibility that these two elements may play an interdependent role in regulating genes in hESC. Our results indicate that amongst 15,760 G4/iM-forming locations, only 15% have 5hmCs associated with them. A detailed analysis of G4/iM-forming locations enriched in 5hmC indicates that most of these locations are in genes that are associated with cell differentiation, proliferation, apoptosis and embryogenesis. The library generated from our analysis is an important resource for investigators exploring the interdependence of these DNA features in regulating expression of selected genes in hESC.

Osteonecrosis of the femoral head (ONFH) is recognized as a common refractory orthopedic disease that causes severe pain and poor quality of life in patients. Puerarin (Pue), a natural isoflavone glycoside, can promote osteogenesis and inhibit apoptosis of bone mesenchymal stem cells (BMSCs), demonstrating its great potential in the treatment of osteonecrosis. However, its low aqueous solubility, fast degradation in vivo, and inadequate bioavailability, limit its clinical application and therapeutic efficacy. Tetrahedral framework nucleic acids (tFNAs) are promising novel DNA nanomaterials in drug delivery. In this study, tFNAs as Pue carriers is used and synthesized a tFNA/Pue complex (TPC) that exhibited better stability, biocompatibility, and tissue utilization than free Pue. A dexamethasone (DEX)-treated BMSC model in vitro and a methylprednisolone (MPS)-induced ONFH model in vivo is also established, to explore the regulatory effects of TPC on osteogenesis and apoptosis of BMSCs. This findings showed that TPC can restore osteogenesis dysfunction and attenuated BMSC apoptosis induced by high-dose glucocorticoids (GCs) through the hedgehog and Akt/Bcl-2 pathways, contributing to the prevention of GC-induced ONFH in rats. Thus, TPC is a promising drug for the treatment of ONFH and other osteogenesis-related diseases., (© 2023 Wiley-VCH GmbH.)

Isothermal nucleic acid amplification techniques have emerged as an important diagnostic tool for clinical applications and food safety inspection. Rolling circle amplification (RCA) is well known for its simple, highly efficient and robust nucleic acid amplification. Besides, RCA excels through its convenient and accessible amplification requirements, making it a promising candidate for point of care testing (POCT). In this review, we firstly introduce the basic principles of RCA cyclization methods, RCA species and RCA optimization strategies. Based on these principles and strategies, we summarize the recent achievements on the design, development and application of RCA biosensors for biosensing. Moreover, we discuss the versatile application of RCA in DNA nanotechnology, where RCA acts as a programable DNA nanomaterials construction tool for bioimaging, drug delivery and therapeutics. Finally, we discuss the current challenges and future perspectives of the RCA technique. • Emerging RCA-based biosensors and nanomaterials are critically reviewed. • Current RCA technique and its development are introduced. • Analytical performances of different RCA-based biosensors were summarized. • Designs and Applications of RCA-based nanomaterials were summarized. • Future challenges of the RCA-based biosensors and nanomaterials are discussed. [ABSTRACT FROM AUTHOR]

Bladder outlet obstruction (BOO) is a prevalent condition arising from urethral stricture, posterior urethral valves, and benign prostatic hyperplasia. Long-term obstruction can lead to bladder remodeling, which is characterized by inflammatory cell infiltration, detrusor hypertrophy, and fibrosis. Until now, there are no efficacious therapeutic options for BOO-induced remodeling. Tetrahedral framework nucleic acids (tFNAs) are a type of novel 3D DNA nanomaterials that possess excellent antifibrotic effects. Here, to determine the treatment effects of tFNAs on BOO-induced remodeling is aimed. Four single-strand DNAs are self-assembled to form tetrahedral framework DNA nanostructures, and the antifibrotic effects of tFNAs are investigated in an in vivo BOO animal model and an in vitro transforming growth factor beta1 (TGF-β1)-induced fibrosis model. The results demonstrated that tFNAs could ameliorate BOO-induced bladder fibrosis and dysfunction by inhibiting M2 macrophage polarization and the macrophage-myofibroblast transition (MMT) process. Furthermore, tFNAs regulate M2 polarization and the MMT process by deactivating the signal transducer and activator of transcription (Stat) and TGF-β1/small mothers against decapentaplegic (Smad) pathways, respectively. This is the first study to reveal that tFNAs might be a promising nanomaterial for the treatment of BOO-induced remodeling., (© 2023 Wiley-VCH GmbH.)

We have fabricated a DNA-based nanofiber created by self-assembly of guanine quadruplex (Hoogsteen base pairing) and double-stranded DNA (Watson-Crick base pairing). When duplexes containing a long stretch of contiguous guanines and single-stranded overhangs are incubated in potassium-containing buffer, the preformed duplexes create high molecular weight species that contain quadruplexes. In addition to observation of these larger species by gel electrophoresis, solutions were analyzed by atomic force microscopy to reveal nanofibers. Analysis of the atomic force microscopy images indicates that fibers form with lengths ranging from 250 to 2,000 nm and heights from 0.45 to 4.0 nm. This work is a first step toward the creation of new structurally heterogeneous (quadruplex/duplex), yet controllable, DNA-based materials exhibiting novel properties suitable for a diverse array of nanotechnology applications [ABSTRACT FROM AUTHOR]

Summary: Freestanding ultrathin nano-membranes (FUN-membranes) are two-dimensional materials of nanoscale thickness (less than 100nm) with little or no substrate support. Recently, there has been an emerging interest to rationally design such membranes for a broad spectrum of appealing applications ranging from lightweight, foldable electronic devices to highly efficient separation and sensing systems. In this review, we aim to summarize the recent developments of FUN-membranes fabricated via an assortment of bottom-up self-assembly strategies. In particular, we will describe the various fabrication methods, characterization approaches, as well as the properties and applications of FUN-membrane materials. [Copyright &y& Elsevier]

Deoxyribonucleic acid (DNA) has been an emerging building block to construct functional biomaterials. Due to their programmable sequences and rich responsiveness, DNA has attracted rising attention in the construction of intelligent nanomaterials with predicable nanostructure and adjustable functions, which has shown great potential in drug delivery. On the one hand, the DNA sequences with molecule recognition, responsiveness, and therapeutic efficacy can be easily integrated to the framework of DNA nanomaterials by sequence designing; on the other hand, the rich chemical groups on DNA molecules provide binding points for other functional units. In this review, we divided the functionalization modules in the construction of DNA nanomaterials into three types, including targeting modules, responsive modules, and therapeutic modules. Based on these modules, five DNA kinds of representative nanomaterials applied in drug delivery were introduced, including DNA nanogel, DNA origami, DNA framework, DNA nanoflower, and DNA hybrid nanosphere. Finally, we discussed the challenges in the transition of DNA materials to clinical applications. We expect that this review can help readers to obtain a deeper understanding of DNA materials, and further promote the development of these intelligent materials to real world's application. This article is categorized under: Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology., (© 2021 Wiley Periodicals LLC.)

[Display omitted] • Metal organic framework-biomineralized DNA nanospheres were developed as CDT agent. • This CDT agent served as nanoenzyme for boosting the intracellular H 2 O 2 concentration. • Tumor acid-activable cascade reactions were exploited for elevating the ROS level in tumor cells. • This therapeutic platform achieved prominent therapeutic efficacy in both in vitro and in vivo assays. Chemodynamic therapy (CDT) has emerged as an innovative treatment strategy for cancer therapy, and yet most of current systems are highly dependent on endogenous H 2 O 2 for hydroxyl radical (OH) generation, leading to limited therapeutic efficacy. Therefore, it is of significant importance to develop CDT agents with efficient H 2 O 2 self-supplying ability for enhanced CDT efficacy. Herein, we report metal organic framework (MOF)-biomineralized DNA nanospheres as CDT agent engineered with tumor-activable cascade reactions for boosting the intracellular H 2 O 2 concentration, thus achieving remarkable antitumor outcome. As a result of tumor acid-induced dissociation of CDT agent, the released Fe2+/Fe3+ triggers Fenton reaction to produce OH and the released GOx enables to catalyze glucose into H 2 O 2 , which synergistically elevates the ROS level in tumor cells and induces ferroptosis. By exploitation of tumor acid-activable cascade reactions for supplying sufficient H 2 O 2 , our CDT agent achieves prominent therapeutic efficacy in both in vitro and in vivo assays. Our work provides a promising strategy to develop CDT agents for improved CDT efficacy. [ABSTRACT FROM AUTHOR]

DNA nanostructures are emerging as a versatile platform for controlled drug delivery as a result of recent progress in production yield and strategies to obtain prolonged stability in biological environments. The construction of nanostructures from this unique biomaterial provides unparalleled control over structural and functional parameters. Recent applications of DNA origami-based nanocarriers for therapeutic drug delivery in preclinical phases highlight them as promising alternatives to conventional nanomaterials, as they benefit from the inherent favorable properties of DNA including biocompatibility and precise spatial addressability. By incorporating targeting aptamers and responsive properties into the nanocarrier design, more selective DNA origami-based nanocarriers are successfully prepared. On the other hand, current systems remain poorly understood in terms of biodistribution, final fate, and controlled drug release. As such, advances are needed to translate this material platform in its full potential for therapeutic applications. [Display omitted] • Advances in prolonged stability of DNA origami allow biomedical applications. • Drug delivery can benefit from the high programmability and biocompatibility of DNA. • Targeting aptamers and responsive drug release enhance drug selectivity. • DNA origami biodistribution and controlled drug release need better understanding. • Surprisingly, DNA origami nanostructure production costs will not hinder translation. [ABSTRACT FROM AUTHOR]

• DNA is used as a universal substrate to develop diverse engineering systems to improve human and environmental health. • The recent progress on the DNA-based engineering systems used in identification, detection, and treatment is summarized. • Future challenges and opportunities in the development of the DNA-based engineering system are provided. Water pollution and the global spread of pathogens pose unexpected and considerable challenges to human and environmental health. Recent developments in DNA-based engineering systems show various real-world applications in ecosystem restoration, medical diagnostics, immune regulation, and drug delivery, providing new opportunities to address these challenges. DNA materials are essentially different from non-biological materials and act as a robust molecular building block with exceptional attributes; these attributes include its genetic function, biocompatibility, nanoscale controllability, programmability, and molecular recognition capability. Unlike traditional systems using separate strategies, the unique properties of DNA molecules enable their use as universal substrates to develop diverse engineering systems and offer a flexible solution concept to current challenges. Here, we outline principles and approaches for the use of three DNA-based engineering subsystems—DNA tracers, DNA barcodes, and DNA hydrogels—in improving human and environmental health in the context of pollution identification, pathogen detection, and medical treatment, with some discussion of typical examples to highlight the focus of current research and envision potential development direction. We believe that this review will contribute to the rational design of DNA-based tracer, barcode and hydrogel system, and the successful integration of these subsystems that are intrinsically interconnected will further demonstrate their synergistic effects on environmental remediation and medical care. [ABSTRACT FROM AUTHOR]

In recent years, tetrahedral framework nucleic acids (tFNAs) have become a hot topic in the field of DNA nanomaterials due to their excellent mechanical, chemical and biological properties. By taking advantage of these merits, tFNAs of varied sizes and modification methods have been designed and applied in diverse fields such as regenerative medicine, biosensors, and tumor treatment to promote human health. This paper reviews the current research progress of tFNAs in human health-related fields, and the future challenges in the clinical applications of tFNAs., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

The past decades have witnessed the development of DNA nanotechnology and the emergence of various spatial DNA nanostructures, from two-dimensions to three-dimensions. The typical example is the tetrahedral framework nucleic acid (tFNA). In this review, we summarize the progress in fabrication, modification of tFNA-based functional systems and their potentials in biomedical applications. Through a one-step assembly process, tFNA is synthesized via four single stranded DNAs with three short sequences complementary to the other sequence of another single strand. Characterizations including polyacrylamide gel electrophoresis, atomic force microscopy, and dynamic light scattering measurement show tFNA as a pyramid-like nanostructure with the size of around 10 nm. Feathered with intrinsic biocompatibility and satisfactory cellular membrane permeability, the first generation of tFNA shows promising capacities in regulating cell biological behavior, promoting tissue regeneration, and immunomodulation. Along with excellent editability and relative biostability in complicated conditions, tFNA could be modified via hanging functional domains on the vertex or side arm and incorporating small-molecular-weight drugs to form the second generation, for reversing multidrug resistance in tumor cells or microorganisms, target therapy, anticancer and antibacterial treatments. The third generation of tFNA is currently tried via a multistep assembly process for stimuli-response and precise drug release. Although tFNAs show promising potentials in cargo delivery, massive efforts still need to be made to improve biostability, maximal load, and structural controllability.

G-quadruplexes (G4s) and i-motifs (iMs) are tetraplex DNA structures. Sequences capable of forming G4/iMs are abundant near the transcription start sites (TSS) of several genes. G4/iMs affect gene expression in vitro. Depending on the gene, the presence of G4/iMs can enhance or suppress expression, making it challenging to discern the underlying mechanism by which they operate. Factors affecting G4/iM structures can provide additional insight into their mechanism of regulation. One such factor is epigenetic modification. The 5-hydroxymethylated cytosines (5hmCs) are epigenetic modifications that occur abundantly in human embryonic stem cells (hESC). The 5hmCs, like G4/iMs, are known to participate in gene regulation and are also enriched near the TSS. We investigated genomic co-localization to assess the possibility that these two elements may play an interdependent role in regulating genes in hESC. Our results indicate that amongst 15,760 G4/iM-forming locations, only 15% have 5hmCs associated with them. A detailed analysis of G4/iM-forming locations enriched in 5hmC indicates that most of these locations are in genes that are associated with cell differentiation, proliferation, apoptosis and embryogenesis. The library generated from our analysis is an important resource for investigators exploring the interdependence of these DNA features in regulating expression of selected genes in hESC. [ABSTRACT FROM AUTHOR]