Monotherapy, especially the use of antibodies targeting vascular endothelial growth factor (VEGF), has shown limitations in treating choroidal neovascularization (CNV) since reactive oxygen species (ROS) also exacerbate CNV formation. Herein, we developed a combination therapy based on a DNA origami platform targeting multiple components of ocular neovascularization. Our study demonstrated that ocular neovascularization was markedly suppressed by intravitreal injection of a rectangular DNA origami sheet modified with VEGF aptamers (Ap) conjugated to an anti-VEGF antibody (aV) via matrix metalloproteinase (MMP)-cleavable peptide linkers in a mouse model of CNV. Typically, the DNA origami-based therapeutic platform selectively accumulates in neovascularization lesions owing to the dual-targeting ability of the aV and Ap, followed by the cleavage of the peptide linker by MMPs to release the antibody. Together, the released antibody and Ap inhibited VEGF activity. Moreover, the residual bare DNA origami could effectively scavenge ROS, reducing oxidative stress at CNV sites and thus maximizing the synergistic effects of inhibiting neovascularization.

Renal ischemia-reperfusion injury (IRI) is a major contributing factor to the development of acute kidney injury (AKI) and has resulted in considerable morbidity and mortality. Persistent inflammatory responses and excessive reactive oxygen species (ROS) in the kidney following IRI can severely delay tissue repair, making it challenging to effectively promote IRI regeneration. Herein, we report an approach to enhance immunotherapy using interleukin-10 (IL-10) to promote IRI regeneration by loading IL-10 onto rectangular DNA origami nanostructures (rDON). rDON can significantly enhance the renal accumulation and retention time of IL-10, enabling it to effectively polarize type 1 macrophages into type 2 macrophages, thereby significantly reducing proinflammatory factors and increasing anti-inflammatory factors. In addition, DNA origami helps mitigate the harmful effects of ROS during renal IRI. The administration of IL-10-loaded DNA origami effectively improves kidney function, resulting in a notable reduction in blood urea nitrogen, serum uric acid, and serum creatinine levels. Our study demonstrates that the integration of anti-inflammatory cytokines within DNA origami holds promise as a strategic approach for cytokine immunotherapy in patients with AKI and other renal disorders.

Staphylococcus aureus (SA) poses a serious risk to human and animal health, necessitating a low-cost and high-performance analytical platform for point-of-care diagnostics. Cellulose paper-based field-effect transistors (FETs) with RNA-cleaving DNAzymes (RCDs) can fulfill the low-cost requirements, however, its high hydrophilicity and lipophilicity hinder biochemical modification and result in low sensitivity, poor mechanical stability and poor fouling performance. Herein, we proposed a controllable self-cleaning FET to simplify biochemical modification and improve mechanical stability and antifouling performance. Then, we constructed an RCD-based DNA nanotree to significantly enhance the sensitivity for SA detection. For controllable self-cleaning FET, 1 H,1 H,2 H,2 H-perfluorodecyltrimethoxysilane based-polymeric nanoparticles were synthesized to decorate cellulose paper and whole carbon nanofilm wires. O2 plasma was applied to regulate to reduce fluorocarbon chain density, and then control the hydrophobic-oleophobic property in sensitive areas. Because negatively charged DNA affected the sensitivity of semiconducting FETs, three Y-shaped branches with low-cost were designed and applied to synthesize an RCD-based DNA-Nanotree based on similar DNA-origami technology, which further improved the sensitivity. The trunk of DNA-Nanotree was composed of RCD, and the canopy was self-assembled using multiple Y-shaped branches. The controllable self-cleaning FET biosensor was applied for SA detection without cultivation, which had a wide linear range from 1 to 105 CFU/mL and could detect a low value of 1 CFU/mL.

Circular dichroism (CD) spectroscopy has been extensively utilized for detecting and distinguishing the chirality of diverse substances and structures. However, CD spectroscopy is inherently weak and conventionally associated with chiral sensing, thus constraining its range of applications. Here, we report a DNA-origami-empowered metasurface sensing platform through the collaborative effect of metasurfaces and DNA origami, enabling achiral/slightly chiral sensing with high sensitivity via the enhanced ΔCD. An anapole metasurface, boasting over 60 times the average optical chirality enhancement, was elaborately designed to synergize with reconfigurable DNA origami. We experimentally demonstrated the detection of achiral/slightly chiral DNA linker strands via the enhanced ΔCD of the proposed platform, whose sensitivity was a 10-fold enhancement compared with the platform without metasurfaces. Our work presents a high-sensitivity platform for achiral/slightly chiral sensing through chiral spectroscopy, expanding the capabilities of chiral spectroscopy and inspiring the integration of multifunctional artificial nanostructures across diverse domains.

DNA nanostructures have been utilized to study biological mechanical processes and construct artificial nanosystems. Many application scenarios necessitate nanodevices able to robustly generate large single molecular forces. However, most existing dynamic DNA nanostructures are triggered by probabilistic hybridization reactions between spatially separated DNA strands, which only non-deterministically generate relatively small compression forces (≈0.4 piconewtons (pN)). Here, an intercalator-triggered dynamic DNA origami nanostructure is developed, where large amounts of local binding reactions between intercalators and the nanostructure collectively lead to the robust generation of relatively large compression forces (≈11.2 pN). Biomolecular loads with different stiffnesses, 3, 4, and 6-helix DNA bundles are efficiently bent by the compression forces. This work provides a robust and powerful force-generation tool for building highly chemo-mechanically coupled molecular machines in synthetic nanosystems.

Nanodevices that function in specific organs or cells are one of the ultimate goals of synthetic biology. The recent progress in DNA nanotechnology such as DNA origami has allowed us to construct nanodevices to deliver a payload (e.g., drug) to the tumor. However, delivery to specific organs remains difficult due to the fragility of the DNA nanostructure and the low targeting capability of the DNA nanostructure. Here, we constructed tough DNA origami that allowed us to encapsulate the DNA origami into lipid-based nanoparticles (LNPs) under harsh conditions (low pH), harnessing organ-specific delivery of the gene of interest (GOI). We found that DNA origami-encapsulated LNPs can increase the functionality of payload GOIs (mRNA and siRNA) inside mouse organs through the contribution from different LNP structures revealed by cryogenic electron microscope (Cryo-EM). These data should be the basis for future organ-specific gene expression control using DNA origami nanodevices.

RNA-based therapeutics have emerged as a promising approach for the treatment of various diseases, including cancer, genetic disorders, and infectious diseases. However, the delivery of RNA molecules into target cells has been a major challenge due to their susceptibility to degradation and inefficient cellular uptake. To overcome these hurdles, DNA-based nano technology offers an unprecedented opportunity as a potential delivery platform for RNA therapeutics. Due to its excellent characteristics such as programmability and biocompatibility, these DNA-based nanostructures, composed of DNA molecules assembled into precise and programmable structures, have garnered significant attention as ideal building materials for protecting and delivering RNA payloads to the desired cellular destinations. In this review, we highlight the current progress in the design and application of three DNA-based nanostructures: DNA origami, lipid-nanoparticle (LNP) technology related to frame guided assembly (FGA), and DNA hydrogel for the delivery of RNA molecules. Their biomedical applications are briefly discussed and the challenges and future perspectives in this field are also highlighted.

The metal plasmonic nanostructure has the optical property of plasmon resonance, which holds great potential for development in nanophotonics, bioelectronics, and molecular detection. However, developing a general and straightforward method to prepare metal plasmonic nanostructures with a controllable size and morphology still poses a challenge. Herein, we proposed a synthesis strategy that utilized a customizable self-assembly template for shape-directed growth of metal structures. We employed gold nanoparticles (AuNPs) as connectors and DNA nanotubes as branches, customizing gold nanoparticle-DNA origami composite nanostructures with different branches by adjusting the assembly ratio between the connectors and branches. Subsequently, various morphologies of plasmonic metal nanostructures were created using this template shape guided strategy, which exhibited enhancement of surface-enhanced Raman scattering (SERS) signals. This strategy provides a new approach for synthesizing metallic nanostructures with multiple morphologies and opens up another possibility for the development of customizable metallic plasmonic structures with broader applications.

Acute lung injury (ALI) is a severe inflammatory lung disease, with high mortality rates. Early intervention by reactive oxygen species (ROS) scavengers could reduce ROS accumulation, break the inflammation expansion chain in alveolar macrophages (AMs), and avoid irreversible damage to alveolar epithelial and endothelial cells. Here, we reported cell-penetrating R9 peptide-modified triangular DNA origami nanostructures (tDONs-R9) as a novel nebulizable drug that could reach the deep alveolar regions and exhibit an enhanced uptake preference of macrophages. tDONs-R9 suppressed the expression of pro-inflammatory cytokines and drove polarization toward the anti-inflammatory M2 phenotype in macrophages. In the LPS-induced ALI mouse model, treatment with nebulized tDONs-R9 alleviated the overwhelming ROS, pro-inflammatory cytokines, and neutrophil infiltration in the lungs. Our study demonstrates that tDONs-R9 has the potential for ALI treatment, and the programmable DNA origami nanostructures provide a new drug delivery platform for pulmonary disease treatment with high delivery efficiency and biosecurity.

DNA nanostructures exhibit versatile geometries and possess sophisticated capabilities not found in other nanomaterials. They serve as customizable nanoplatforms for orchestrating the spatial arrangement of molecular components, such as biomolecules, antibodies, or synthetic nanomaterials. This is achieved by incorporating oligonucleotides into the design of the nanostructure. In the realm of drug delivery to cancer cells, there is a growing interest in active targeting assays to enhance efficacy and selectivity. The active targeting approach involves a \"key-lock\" mechanism where the carrier, through its ligand, recognizes specific receptors on tumor cells, facilitating the release of drugs. Various DNA nanostructures, including DNA origami, Tetrahedral, nanoflower, cruciform, nanostar, nanocentipede, and nanococklebur, can traverse the lipid layer of the cell membrane, allowing cargo delivery to the nucleus. Aptamers, easily formed in vitro, are recognized for their targeted delivery capabilities due to their high selectivity for specific targets and low immunogenicity. This review provides a comprehensive overview of recent advancements in the formation and modification of aptamer-modified DNA nanostructures within drug delivery systems.