A DNA tetrahedron-based nanosuit for efficient delivery of amifostine and multi-organ radioprotection.

Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages to normal cells and organs, leading to serious physiological and even life-threatening consequences. Amifostine (AMF) is a validated radioprotectant extensively applied in radiation and chemotherapy medicine, but the short half-life limits its bioavailability and clinical applications, remaining as a great challenge to be addressed. DNA-assembled nanostructures especially the tetrahedral framework nucleic acids (tFNAs) are promising nanocarriers with preeminent biosafety, low biotoxicity, and high transport efficiency. The tFNAs also have a relative long-term maintenance for structural stability and excellent endocytosis capacity. We therefore synthesized a tFNA-based delivery system of AMF for multi-organ radioprotection (tFNAs@AMF, also termed nanosuit). By establishing the mice models of accidental total body irradiation (TBI) and radiotherapy model of Lewis lung cancer, we demonstrated that the nanosuit could shield normal cells from IR-induced DNA damage by regulating the molecular biomarkers of anti-apoptosis and anti-oxidative stress. In the accidental total body irradiation (TBI) mice model, the nanosuit pretreated mice exhibited satisfactory alteration of superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents, and functional recovery of hematopoietic system, reducing IR-induced pathological damages of multi-organ and safeguarding mice from lethal radiation. More importantly, the nanosuit showed a selective radioprotection of the normal organs without interferences of tumor control in the radiotherapy model of Lewis lung cancer. Based on a conveniently available DNA tetrahedron-based nanocarrier, this work presents a high-efficiency delivery system of AMF with the prolonged half-life and enhanced radioprotection for multi-organs. Such nanosuit pioneers a promising strategy with great clinical translation potential for radioactivity protection.

Comparison of neurally adjusted ventilatory assist and synchronized intermittent mandatory ventilation in preterm infants after patent ductus arteriosus ligation: a retrospective study.

OBJECTIVE: This study aimed to compare the efficacy of neurally adjusted ventilatory assist (NAVA) to synchronized intermittent mandatory ventilation (SIMV) in preterm infants requiring mechanical ventilation after patent ductus arteriosus (PDA) ligation. METHODS: A retrospective analysis was conducted on intubated preterm infants who underwent PDA ligation at our hospital from July 2021 to January 2023. Infants were divided into NAVA or SIMV groups based on the ventilation mode after surgery. RESULTS: Fifty preterm infants were included. During treatment, peak inspiratory pressure (PIP) and mean airway pressure (MAP) were lower with NAVA compared to SIMV (PIP: 19.1 ± 2.9 vs. 22.4 ± 3.6 cmH2O, P < 0.001; MAP: 9.1 ± 1.8 vs. 10.9 ± 2.7 cmH2O, P = 0.002). PaO2 and PaO2/FiO2 were higher with NAVA (PaO2: 94.0 ± 11.7 vs. 84.8 ± 15.8 mmHg, P = 0.031; PaO2/FiO2: 267 [220-322] vs. 232 [186-290] mmHg, P = 0.025). Less sedation was required with NAVA (midazolam: 1.5 ± 0.5 vs. 1.1 ± 0.3 µg/kg/min, P < 0.001). CONCLUSION: Compared to SIMV, early use of NAVA post PDA ligation in preterm infants was associated with decreased PIP and MAP. Early NAVA was also associated with reduced sedation needs and improved oxygenation. However, further studies are warranted to quantify the benefits of NAVA ventilation.

Harnessing tetrahedral framework nucleic acids for enhanced delivery of microRNA-149-3p: A new frontier in oral squamous cell carcinoma therapy.

Oral squamous cell carcinoma (OSCC), a type of malignant tumour that primarily occurs in the oral mucosa, has drawn considerable attention owing to its aggressive growth and potentially high metastatic rate. Surgical resection is the primary treatment method for OSCC and is typically combined with radiation therapy and chemotherapy. microRNA-149-3p (miR-149) is a negative regulator of the Pi3k/Akt pathway and can effectively inhibit the proliferation of tumour cells. However, the application of miR-149 is limited owing to its relatively low efficiency of cellular uptake and poor stability when used alone. To overcome these challenges, this study adopted a novel nucleic acid nanostructured material, tetrahedral framework nucleic acids (tFNAs). The use of tFNAs as carriers to assemble the T-miR-149 complex reduced the expression of Pi3k and Akt involved in tumorigenesis and alterations in proteins related to cell apoptosis. The results indicated that the bionic drug delivery system has an effective tumour suppressive effect on OSCC in mice, revealing its potential clinical value in the treatment of OSCC.

Framework Nucleic Acids-Based VEGF Signaling Activating System for Angiogenesis: A Dual Stimulation Strategy.

Angiogenesis is crucial for tissue engineering, wound healing, and regenerative medicine. Nanomaterials constructed based on specific goals can be employed to activate endogenous growth factor-related signaling. In this study, based on the conventional single-stranded DNA self-assembly into tetrahedral framework nucleic acids (tFNAs), the Apt02 nucleic acid aptamer and dimethyloxallyl glycine (DMOG) small molecule are integrated into a complex via a template-based click chemistry reaction and toehold-mediated strand displacement reaction. Thus, being able to simulate the VEGF (vascular endothelial growth factor) function and stabilize HIF (hypoxia-inducible factor), a functional whole is constructed and applied to angiogenesis. Cellular studies demonstrate that the tFNAs-Apt02 complex (TAC) has a conspicuous affinity to human umbilical vein endothelial cells (HUVECs). Further incubation with DMOG yields the tFNAs-Apt02-DMOG complex (TACD), which promotes VEGF secretion, in vitro blood vessel formation, sprouting, and migration of HUVECs. Additionally, TACD enhances angiogenesis by upregulating the VEGF/VEGFR and HIF signaling pathways. Moreover, in a diabetic mouse skin defect repair process, TACD increases blood vessel formation and collagen deposition, therefore accelerating wound healing. The novel strategy simulating VEGF and stabilizing HIF promotes blood-vessel formation in vivo and in vitro and has the potential for broad applications in the vascularization field.

MicroRNA-29c-tetrahedral framework nucleic acids: Towards osteogenic differentiation of mesenchymal stem cells and bone regeneration in critical-sized calvarial defects.

Certain miRNAs, notably miR29c, demonstrate a remarkable capacity to regulate cellular osteogenic differentiation. However, their application in tissue regeneration is hampered by their inherent instability and susceptibility to degradation. In this study, we developed a novel miR29c delivery system utilising tetrahedral framework nucleic acids (tFNAs), aiming to enhance its stability and endocytosis capability, augment the efficacy of miR29c, foster osteogenesis in bone marrow mesenchymal stem cells (BMSCs), and significantly improve the repair of critical-sized bone defects (CSBDs). We confirmed the successful synthesis and biocompatibility of sticky ends-modified tFNAs (stFNAs) and miR29c-modified stFNAs (stFNAs-miR29c) through polyacrylamide gel electrophoresis, microscopy scanning, a cell counting kit-8 assay and so on. The mechanism and osteogenesis effects of stFNAs-miR29c were explored using immunofluorescence staining, western blotting, and reserve transcription quantitative real-time polymerase chain reaction. Additionally, the impact of stFNAs-miR29c on CSBD repair was assessed via micro-CT and histological staining. The nano-carrier, stFNAs-miR29c was successfully synthesised and exhibited exemplary biocompatibility. This nano-nucleic acid material significantly upregulated osteogenic differentiation-related markers in BMSCs. After 2 months, stFNAs-miR29c demonstrated significant bone regeneration and reconstruction in CSBDs. Mechanistically, stFNAs-miR29c enhanced osteogenesis of BMSCs by upregulating the Wnt signalling pathway, contributing to improved bone tissue regeneration. The development of this novel nucleic acid nano-carrier, stFNAs-miR29c, presents a potential new avenue for guided bone regeneration and bone tissue engineering research.

Modulation of Cerebrospinal Fluid Dysregulation via a SPAK and OSR1 Targeted Framework Nucleic Acid in Hydrocephalus.

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.

A DNA nanostructure-Hif-1α inducer complex as novel nanotherapy against cisplatin-induced acute kidney injury.

Since its discovery in 1978, cisplatin-based chemotherapy regimens have served a pivotal role in human cancer treatment, saving millions of lives. However, its high risk still poses a significant challenge for cisplatin-induced acute kidney injury (AKI), which occurs in 30% of cisplatin-treated patients. Unfortunately, no effective solution for preventing or managing this severe complication, which greatly impacts its clinical administration. Kidney is the main organ injured by cisplatin, and the injury is related to cisplatin-induced cell apoptosis and DNA injury. Therefore, to achieve the safe use of cisplatin in tumour treatment, the key lies in identifying a kidney treatment that can effectively minimize cisplatin nephrotoxicity. Here, we successfully synthesized and applied a DNA-nanostructure complex, named TFG, which contains tetrahedral framework nucleic acids (tFNAs) and FG-4592, a novel Hif-1α inducer. As cargo, TFG is composed entirely of DNA strands. It possesses low nephrotoxicity and renal aggregation properties while FG-4592 is able to relieve renal injury by downregulating the apoptosis signal pathways. And it can relieve cisplatin-induced renal injury when taken cisplatin treatment. This work aims to enhance chemotherapy protection in tumour patients by using TFG, a DNA-based nanomedicines to kidney. This work has the potential to revolutionize the treatment of renal diseases, particularly drug-induced kidney injury, leading to improved clinical outcomes.

Effect of tetrahedral framework nucleic acids on the reconstruction of tendon-to-bone injuries after rotator cuff tears.

Clinicians and researchers have always faced challenges in performing surgery for rotator cuff tears (RCT) due to the intricate nature of the tendon-bone gradient and the limited long-term effectiveness. At the same time, the occurrence of an inflammatory microenvironment further aggravates tissue damage, which has a negative impact on the regeneration process of mesenchymal stem cells (MSCs) and eventually leads to the production of scar tissue. Tetrahedral framework nucleic acids (tFNAs), novel nanomaterials, have shown great potential in biomedicine due to their strong biocompatibility, excellent cellular internalisation ability, and unparalleled programmability. The objective of this research was to examine if tFNAs have a positive effect on regeneration after RCTs. Experiments conducted in a controlled environment demonstrated that tFNAs hindered the assembly of inflammasomes in macrophages, resulting in a decrease in the release of inflammatory factors. Next, tFNAs were shown to exert a protective effect on the osteogenic and chondrogenic differentiation of bone marrow MSCs under inflammatory conditions. The in vitro results also demonstrated the regulatory effect of tFNAs on tendon-related protein expression levels in tenocytes after inflammatory stimulation. Finally, intra-articular injection of tFNAs into a rat RCT model showed that tFNAs improved tendon-to-bone healing, suggesting that tFNAs may be promising tendon-to-bone protective agents for the treatment of RCTs.

Tetrahedral DNA loaded siCCR2 restrains M1 macrophage polarization to ameliorate pulmonary fibrosis in chemoradiation-induced murine model.

Idiopathic pulmonary fibrosis (IPF) is a chronic lethal disease in the absence of demonstrated efficacy for preventing progression. Although macrophage-mediated alveolitis is determined to participate in myofibrotic transition during disease development, the paradigm of continuous macrophage polarization is still under-explored due to lack of proper animal models. Here, by integrating 2.5 U/kg intratracheal Bleomycin administration and 10 Gy thorax irradiation at day 7, we generated a murine model with continuous alveolitis-mediated fibrosis, which mimics most of the clinical features of our involved IPF patients. In combination with data from scRNA-seq of patients and a murine IPF model, a decisive role of CCL2/CCR2 axis in driving M1 macrophage polarization was revealed, and M1 macrophage was further confirmed to boost alveolitis in leading myofibroblast activation. Multiple sticky-end tetrahedral framework nucleic acids conjunct with quadruple ccr2-siRNA (FNA-siCCR2) was synthesized in targeting M1 macrophages. FNA-siCCR2 successfully blocked macrophage accumulation in pulmonary parenchyma of the IPF murine model, thus preventing myofibroblast activation and leading to the disease remitting. Overall, our studies lay the groundwork to develop a novel IPF murine model, reveal M1 macrophages as potential therapeutic targets, and establish new treatment strategy by using FNA-siCCR2, which are highly relevant to clinical scenarios and translational research in the field of IPF.

Transcutaneous Immunotherapy for RNAi: A Cascade-Responsive Decomposable Nanocomplex Based on Polyphenol-Mediated Framework Nucleic Acid in Psoriasis.

Skin is the first barrier against external threats, and skin immune dysfunction leads to multiple diseases. Psoriasis is an inflammatory, chronic, common, immune-related skin disease that affects more than 125 million people worldwide. RNA interference (RNAi) therapy is superior to traditional therapies, but rapid degradation and poor cell uptake are the greatest obstacles to its clinical transformation. The transdermal delivery of siRNA and controllable assembly/disassembly of nanodrug delivery systems can maximize the therapeutic effect. Tetrahedral framework nucleic acid (tFNA) is undoubtedly the best carrier for the transdermal transport of genes due to its excellent noninvasive transdermal effect and editability. The authors combine acid-responsive tannic acid (TA), RNase H-responsive sequences, siRNA, and tFNA into a novel transdermal RNAi drug with controllable assembly and disassembly: STT. STT has heightened resistance to enzyme, serum, and lysosomal degradation, and its size is similar to that of tFNA, enabling easy transdermal transport. After transdermal administration, STT can specifically silence nuclear factor kappa-B (NF-κB) p65, thereby maintaining the stability of the skin's microenvironment and reshaping normal skin immune defense. This work demonstrates the advantages of STT in RNAi therapy and the potential for future treatment of skin-related diseases.

Emerging applications of anti-angiogenic nanomaterials in oncotherapy.

Angiogenesis is the process of generating new blood vessels from pre-existing vasculature. Under normal conditions, this process is delicately controlled by pro-angiogenic and anti-angiogenic factors. Tumor cells can produce plentiful pro-angiogenic molecules promoting pathological angiogenesis for uncontrollable growth. Therefore, anti-angiogenic therapy, which aims to inhibit tumor angiogenesis, has become an attractive approach for oncotherapy. However, classic anti-angiogenic agents have several limitations in clinical use, such as lack of specific targeting, low bioavailability, and poor therapeutic outcomes. Hence, alternative angiogenic inhibitors are highly desired. With the emergence of nanotechnology, various nanomaterials have been designed for anti-angiogenesis purposes, offering promising features like excellent targeting capabilities, reduced side effects, and enhanced therapeutic efficacy. In this review, we describe tumor vascular features, discuss current dilemma of traditional anti-angiogenic medicines in oncotherapy, and underline the potential of nanomaterials in tumor anti-angiogenic therapy. Moreover, we discuss the current challenges of anti-angiogenic cancer treatment. We expect that this summary of anti-angiogenic nanomaterials in oncotherapy will offer valuable insights, facilitating their extensive applications in the future.

A Mitochondrial Nanoguard Modulates Redox Homeostasis and Bioenergy Metabolism in Diabetic Peripheral Neuropathy.

As a major late complication of diabetes, diabetic peripheral neuropathy (DPN) is the primary reason for amputation. Nevertheless, there are no wonder drugs available. Regulating dysfunctional mitochondria is a key therapeutic target for DPN. Resveratrol (RSV) is widely proven to guard mitochondria, yet the unsatisfactory bioavailability restricts its clinical application. Tetrahedral framework nucleic acids (tFNAs) are promising carriers due to their excellent cell entrance efficiency, biological safety, and structure editability. Here, RSV was intercalated into tFNAs to form the tFNAs-RSV complexes. tFNAs-RSV achieved enhanced stability, bioavailability, and biocompatibility compared with tFNAs and RSV alone. With its treatment, reactive oxygen species (ROS) production was minimized and reductases were activated in an in vitro model of DPN. Besides, respiratory function and adenosine triphosphate (ATP) production were enhanced. tFNAs-RSV also exhibited favorable therapeutic effects on sensory dysfunction, neurovascular deterioration, demyelination, and neuroapoptosis in DPN mice. Metabolomics analysis revealed that redox regulation and energy metabolism were two principal mechanisms that were impacted during the process. Comprehensive inspections indicated that tFNAs-RSV inhibited nitrosation and oxidation and activated reductase and respiratory chain. In sum, tFNAs-RSV served as a mitochondrial nanoguard (mito-guard), representing a viable drilling target for clinical drug development of DPN.

Self-Assembled Multivalent Aptamer Drug Conjugates: Enhanced Targeting and Cytotoxicity for HER2-Positive Gastric Cancer.

Antibody drug conjugates (ADCs) have shown promise to be the mainstream chemotherapeutics for advanced HER2-positive cancers, yet the issues of poor drug delivery efficiency, limited chemotherapeutic effects, severe immune responses, and drug resistance remain to be addressed before the clinical applications of ADCs. The DNA aptamer-guided drug conjugates (ApDCs) are receiving growing attention for specific tumors due to their excellent tumor affinity and low cost. Therefore, developing a multivalent ApDC nanomedicine by combining anti-HER2 aptamer (HApt), tetrahedral framework nucleic acid (tFNA), and deruxtecan (Dxd) together to form HApt-tFNA@Dxd might help to address these concerns. In this study, the HER2-targeted DNA aptamer modified DNA tetrahedron (HApt-tFNA) was employed as a system for drug delivery, and the adoption of tFNA could effectively enlarge the drug-loading rate compared to aptamer-guided ApDCs previously reported. Compared with free Dxd and tFNA@Dxd, HApt-tFNA@Dxd showed better structural stability, excellent targeted cytotoxicity to HER2-positive gastric cancer, and increased tissue aggregation ability in tumors. These features and superiorities make HApt-tFNA@Dxd a promising chemotherapeutic medicine for HER2-positive tumors. Our work developed a new targeting nanomedicine by combining DNA nanomaterials and chemotherapeutic agents, which represents a critical advance toward developing novel DNA-based nanomaterials and promoting their potential applications for HER2-positive cancer therapy.

Reactive A1 Astrocyte-Targeted Nucleic Acid Nanoantiepileptic Drug Downregulating Adenosine Kinase to Rescue Endogenous Antiepileptic Pathway.

Resistance to traditional antiepileptic drugs is a major challenge in chronic epilepsy treatment. MicroRNA-based gene therapy is a promising alternative but has demonstrated limited efficacy due to poor blood-brain barrier permeability, cellular uptake, and targeting efficiency. Adenosine is an endogenous antiseizure agent deficient in the epileptic brain due to elevated adenosine kinase (ADK) activity in reactive A1 astrocytes. We designed a nucleic acid nanoantiepileptic drug (tFNA-ADKASO@AS1) based on a tetrahedral framework nucleic acid (tFNA), carrying an antisense oligonucleotide targeting ADK (ADKASO) and A1 astrocyte-targeted peptide (AS1). This tFNA-ADKASO@AS1 construct effectively reduced brain ADK, increased brain adenosine, mitigated aberrant mossy fiber sprouting, and reduced the recurrent spontaneous epileptic spike frequency in a mouse model of chronic temporal lobe epilepsy. Further, the treatment did not induce any neurotoxicity or major organ damage. This work provides proof-of-concept for a novel antiepileptic drug delivery strategy and for endogenous adenosine as a promising target for gene-based modulation.

DNA Tetrahedra-Based Delivery of MicroRNA-22 to Reduce Depressive Symptoms in Mice.

Major depressive disorder (MDD) is a common illness with an increasing lifetime prevalence. Thus, an increasing number of studies have investigated the association between MDD and microRNAs (miRNAs), which are a novel approach for treating depression. However, the therapeutic potential of miRNA-based strategies has several limitations. To overcome these limitations, DNA tetrahedra (TDNs) have been used as piggyback materials. In this study, we successfully used TDNs as carriers of miRNA-22-3p (miR-22-3p) and synthesized a novel DNA nanocomplex (TDN-miR-22-3p), which was used in a lipopolysaccharide (LPS)-induced depression cell model. The results suggest that miR-22-3p may regulate inflammation by regulating phosphatase and tensin homologue (PTEN), an important regulatory molecule in the PI3K/AKT pathway, and downregulating the expression of NLRP3. We further validated the role of TDN-miR-22-3p in vivo using an LPS-induced animal model of depression. The results indicate that it ameliorated depression-like behavior and attenuated the expression of inflammation-related factors in mice. This study demonstrates the establishment of a straightforward and efficacious miRNA delivery system and the potential of TDNs as therapeutic vectors and tools for mechanistic studies. To the best of our knowledge, this is the first study to use TDNs in combination with miRNAs to treat depression.

Nano shield: a new tetrahedral framework nucleic acids-based solution to radiation-induced mucositis.

Radiation-induced oral mucositis (RIOM) is considered to be one of the most important public health problems today, affecting the overall well-being of millions of patients who have received radiotherapy. Nevertheless, the field of preventing and treating RIOM is still widely unexplored. Curcumin (Cur) with its promising anti-inflammatory and antioxidant properties is accompanied with obstacles in application, including poor dissolubility, instability and low bioavailability. In this study, a tetrahedral framework nucleic acid drug delivery system (TFNAS) was synthesized and established using a novel method to carry Cur (Cur-TFNAS) for efficient drug delivery. The results showed that Cur-TFNAS enhanced the antioxidant capacity of human oral mucosal keratin-forming cells (HOKs) compared to free Cur and TFNAS. Meanwhile, Cur-TFNAS reduced DNA damage and shielded the cells from inflammatory factors. A similar result was also well documented in vivo. Herein, we consider that Cur-TFNAS acts as a nano-shield for preventing radiation oral mucositis and shows important clinical value in the future.

Tetrahedral-Framework Nucleic Acid Loaded with MicroRNA-155 Enhances Immunocompetence in Cyclophosphamide-Induced Immunosuppressed Mice by Modulating Dendritic Cells and Macrophages.

Nanomaterials are often used as immunomodulators because they can be tailored by a controllable process. In this work, a complex based on a tetrahedral framework nucleic acid delivery system and MicroRNA-155, known as T-155, is synthesized for the modulation of immunosuppression. In vivo, T-155 ameliorated spleen and thymus damage and hematopoiesis suppression in cyclophosphamide-induced immunosuppressed mice by promoting T-cell proliferation to resist oxidative stress. In vitro, T-155 induced immature dendritic cells (DCs) to differentiate into mature DCs by the ERK1/2 pathway and converted M0 macrophages (Mφ) into the M1 type by the NF-κB pathway to enhance the surveillance capabilities of antigen-presenting cells. The experimental results suggest that T-155 has therapeutic potential as an immunomodulator for immunosuppression.

A dynamic DNA tetrahedron framework for active targeting.

An active targeting strategy-enabled DNA tetrahedron delivery vehicle could facilitate stable drug encapsulation and stimuli-responsive on-demand release, building a universal platform for different drug delivery requirements. Owing to the excellent biocompatible nature, programmability and remarkable cell and tissue permeability, the tetrahedral DNA nanostructure (TDN) has proven its value in the delivery of various bioactive molecules. We previously described this as a static multifunctional complex in our earlier protocol. However, static structures and passive targeting behavior might introduce off-target effects under complicated biological conditions. Therefore, in this Protocol Extension, we present a major update of the TDN delivery vehicle enabling an active targeting strategy to be used for stimuli-sensitive conformation changes and on-site cargo release, which could avoid drawbacks, including complex and time-consuming fabrication processes and undetermined cell penetration ability of other DNA-based delivery vehicles. Upon exquisite design of TDN size based on cargo type, one-pot annealing is applied to fabricate the Tiamat-designed TDN exoskeleton. Then the design of the dynamic DNA apparatus can be based on the target and environmental stimuli, including DNA strand hybridization-based and pH-sensitive DNA apparatus, and careful titration of strand lengths and mismatches is achieved using polyacrylamide and agarose gel electrophoresis, or fluorophore modifications. Finally, cargo loading strategies are designed, including site and stand titration and cargo encapsulation verification. The dynamic structures show promising targetability and effectiveness in antitumor and anti-inflammatory treatment in vitro and in vivo. Assembly and characterization in the lab takes ~5 d, and the timing for the verification of biostability and biological applications depends on the uses.

Tetrahedral framework nucleic acids inhibit pathological neovascularization and vaso-obliteration in ischaemic retinopathy via PI3K/AKT/mTOR signalling pathway.

This study aimed to explore the effect and the molecular mechanism of tetrahedral framework nucleic acids (tFNAs), a novel self-assembled nanomaterial with excellent biocompatibility and superior endocytosis ability, in inhibition of pathological retinal neovascularization (RNV) and more importantly, in amelioration of vaso-obliteration (VO) in ischaemic retinopathy. tFNAs were synthesized from four single-stranded DNAs (ssDNAs). Cell proliferation, wound healing and tube formation assays were performed to explore cellular angiogenic functions in vitro. The effects of tFNAs on reducing angiogenesis and inhibiting VO were explored by oxygen-induced retinopathy (OIR) model in vivo. In vitro, tFNAs were capable to enter endothelial cells (ECs), inhibit cell proliferation, tube formation and migration under hypoxic conditions. In vivo, tFNAs successfully reduce RNV and inhibit VO in OIR model via the PI3K/AKT/mTOR/S6K pathway, while vascular endothelial growth factor fusion protein, Aflibercept, could reduce RNV but not inhibit VO. This study provides a theoretical basis for the further understanding of RNV and suggests that tFNAs might be a novel promising candidate for the treatment of blind-causing RNV.

Improved Tumor Infiltration and Immunomodulation for Tumor Therapy: A Pathway Based on Tetrahedral Framework Nucleic Acids Coupled Bacterial Nanocells.

Growing evidence indicates that the tumor microenvironment (TME) can be combined with other therapeutic modalities, including cytotoxic chemotherapy and targeted therapies, to produce unanticipated results in oncology treatment. Here, we proposed a novel bacterial nanomaterial capable of targeting peritumoral biofilm and modulating TME. It was based on tetrahedral framework nucleic acids (T) that were chemically attached to aptamer AS1411 and 5-fluorouracil (AT5). Additionally, the oral pathogenic bacterium Streptococcus mutans (S.m) was employed as a biocarrier for synergetic biofilm targeting and immunomodulation. In this article, the effect of AT5-coupled S.m-derived nanocells (S.m-AT5) was investigated in vitro and in vivo. Due to bacteria aggregation in the tumor-specific biofilm, these nanocells released greater medication concentrations. Furthermore, they exerted an immunomodulatory effect by stimulating the maturation of dendritic cells (DCs) and regulation of T cells. This chemo-immunostimulation combination has a powerful antitumor impact. It may also be an advanced approach for boosting the survival rate of cancer patients.