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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.

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.)

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.)

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., (© 2024 Wiley-VCH GmbH.)

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.)

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., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

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.)

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.)