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Root resorption occurs outside the root or within the root canal. Regardless of its region, root resorption is irreversible and in severe cases, may even cause tooth loss. Clinically, the external surface root resorption is usually a side effect of orthodontic tooth movement. However, it is frustrating to note that there are almost no effective treatment strategies for orthodontically induced root resorption (OIRR) due to the complexity and ambiguity of etiology. In the current study, we successfully fabricated a delivery complex, reduced graphene oxide nanosheet loading with tetrahedral framework nucleic acids (tFNAs-rGO) through self-assembly. No significant cytotoxicity or organ-toxicity of the tFNAs-rGO complex was observed in cell counting kit-8 assay (CCK-8) and hematoxylin-eosin (HE) staining. Histological staining such as tartrate-resistant acid phosphatase (TRAP) staining and Micro-CT three-dimensional reconstruction were employed to explore the dynamic changes of root and peri-root tissues in OIRR mice. In vitro, we developed an induction microenvironment to testify the effects of the tFNAs-rGO delivery complex on periodontal ligament cells (PDLCs) and macrophages by quantitative RT-PCR, western blot, and immunofluorescence staining. The data showed the reduced the region of root resorption and downregulated osteoclastic activity in OIRR by the tFNAs-rGO complex treatment. Furthermore, our study demonstrated that the tFNAs-rGO delivery complex enhanced osteogenic differentiation of PDLCs and facilitated M2-phenotype polarization of macrophages to ameliorate OIRR. Collectively, the insight into the nanoscale dual-functional tFNAs-rGO delivery complex regulating the cell populations of PDLCs and macrophages in the root resorption remodeling proposes a promising therapeutic strategy for orthodontically induced root resorption., Competing Interests: Declarations Ethics approval and consent to participate Animal studies were approved by the ethics committee, Fujian Medical University under document number IACUC FJMU 2024-Y-0609. Consent for publication All authors read and agreed to submit the manuscript. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Ferroptosis represents a nonapoptotic type of programmed cell death induced by excessive intracellular iron accumulation. Ferroptosis is an essential driver of the pathogenesis of Alzheimer's disease (AD). Tetrahedral framework nucleic acids (tFNAs) are a novel type of nanoparticle with superior antiapoptotic capacity and excellent biocompatibility. However, the effect of tFNAs on Aβ triggered ferroptosis, cognitive and synaptic impairments in AD remains unknown., Methods: N2a cells were treated with Aβ combined with/without tFNAs. Cell viability and levels of Fe 2+ , lipid peroxidation, MDA, LDH, and GSH were examined. RNA sequencing was applied to explore dysregulated ferroptosis related genes. Seven-month-old APP/PS1 mice were intranasally administrated with tFNAs for two weeks. Fluorescence imaging was used to detect the tFNAs distribution in the brain. Novel object recognition (NOR) test followed by Morris water maze (MWM) was used to test the learning and memory performance of mice. Golgi staining, Western blot, and immunofluorescence staining were used to examine synaptic plasticity., Results: tFNAs promoted cell viability and GSH levels, reduced the levels of Fe 2+ , lipid peroxidation, MDA, and LDH in N2a cells treated with Aβ. RNA sequencing revealed that tFNAs reversed the promotive effect of Aβ on ferroptosis driver Atf3 gene and suppressive effect on ferroptosis suppressors Rrm2 and Furin genes. Fluorescence imaging confirmed the brain infiltration of tFNAs. tFNAs rescued synaptic and memory impairments, and ferroptosis in seven-month-old APP/PS1 mice., Conclusions: Collectively, tFNAs inhibited Aβ-mediated ferroptosis and ameliorated cognitive and synaptic impairments in AD mice. tFNAs may serve as novel option to deal with AD., (© 2024. The Author(s).)

Complexes of extracellular nucleic acids (NAs) with endogenous proteins or peptides, such as LL37, break immune balance and cause autoimmune diseases, whereas NAs with arginine-enriched peptides do not. Inspired by this, we synthesize a polyarginine nanoparticle PEG-TK-NP Arg , which effectively inhibits Toll-like receptor-9 (TLR9) activation, in contrast to LL37. To explore the discrepancy effect of PEG-TK-NP Arg and LL37, we evaluate the periodic structure of PEG-TK-NP Arg -NA and LL37-NA complexes using small-angle X-ray scattering. LL37-NA complexes have a larger inter-NA spacing that accommodates TLR9, while the inter-NA spacing in PEG-TK-NP Arg -NA complexes mismatches with the cavity of TLR9, thus inhibiting an interaction with multiple TLR9s, limiting their clustering and damping immune induction. Subsequently, the inhibitory inflammation effect of PEG-TK-NP Arg is proved in an animal model of rheumatoid arthritis. This work on how the scavenger-NA complexes inhibit the immune response may facilitate proof-of-concept research translating to clinical application., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Worldwide, osteoarthritis (OA) is regarded as the most widespread, distressing, and limiting chronic disease that affects degenerative joints. Currently, there is no treatment available to modify the progression of OA. The pathogenesis of OA is significantly linked with oxidative stress and pyroptosis. Astaxanthin (Ast) is a natural ketocarotenoid pigment with potent antioxidant activity and is shown to effectively alleviate cartilage damage in OA. However, its bioavailability is greatly limited due to poor water solubility, high sensitivity to light, temperature, and pH. In this study, Ast-loaded tetrahedral framework nucleic acids (tFNAs) or tFNA/Ast complexes (TAC) for Ast delivery are developed. Compared with free Ast and tFNA alone, TAC exhibits improved drug stability and cellular uptake. Most importantly, TAC effectively protects chondrocytes against oxidative stress-induced pyroptosis while promoting extracellular matrix anabolism by chondrocytes, and ultimately alleviates cartilage damage in a mouse destabilization of the medial meniscus (DMM) model. Thus, TAC holds great promise for the treatment of OA patients., (© 2024 Wiley‐VCH GmbH.)

Retinal ischemia/reperfusion injury (RI/R) is a common pathological process in ophthalmic diseases, which can cause severe visual impairment. The mechanisms underlying RI/R damage and repair are still unclear. Scholars are actively exploring effective intervention strategies to restore impaired visual function. With the development of nucleic acid nanomaterials, tetrahedral framework nucleic acids (tFNAs) have shown promising therapeutic potential in various fields such as stem cells, biosensors, and tumour treatment due to their excellent biological properties. Besides, miRNA-22-3p (miR-22), as an important regulatory factor in neural tissue, has been proven to have positive effects in various neurodegenerative diseases. By stably constructing a complex of tetrahedral framework nucleic acids miR22 (tFNAs-miR22), we observed that tFNAs-miR22 had a positive effect on the repair of RI/R injury in retinal neural tissue. Previous studies have shown that tFNAs can effectively deliver miR-22 into damaged retinal neurons, subsequently exerting neuroprotective effects. Interestingly, we found that there was a certain synergistic effect between tFNAs and miR-22. tFNAs-miR22 can selectively activated the ERK1/2 signalling pathway to reduce neuronal apoptosis, accelerate cell proliferation, and restore synaptic functional activity. In this study, we established a simple yet effective small molecule drug for RI/R treatment which may become a promising neuroprotectant for treating this type of vision impairment disease in the future., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Metastatic osteosarcoma is a commonly seen malignant tumor in adolescents, with a five year survival rate of approximately 20% and a lack of treatment options. Osteosarcoma cancer stem cells are considered to be important drivers of the metastasis of osteosarcoma, and therefore their clearance is considered a promising strategy for treating metastatic osteosarcoma. In the relevant literature, retinoic acid (ATRA) is considered effective for eliminating osteosarcoma stem cells, but it has some inherent disadvantages, including poor solubility, difficulty in entering cells, and structural instability. Tetrahedral framework nucleic acids (tFNAs) are a type of nanoparticles that can carry small-molecule drugs into cells to exert therapeutic effects. Therefore, we designed and synthesized a nanoparticle named T-ATRA by using tFNAs to load ATRA and studied its effect in a nude mouse model. T-ATRA is more effective than ATRA in the clearance of osteosarcoma stem cells and in inhibiting osteosarcoma cell metastasis via the Wnt signaling pathway, thus prolonging the survival time of nude mice with osteosarcoma.

Osteoporosis is a disease that plagues the world, the complications of which, spinal fractures and hip fractures, seriously endanger the health of the elderly. At present, the main treatment for osteoporosis is anti-osteoporosis drugs, some of which, however, have poor efficacy and side effects. Thus, the development of new drugs for the treatment of osteoporosis is of clinical significance. Berberine (BBR) has a good therapeutic effect on osteoporosis, but its poor solubility and instability limit its effect. Tetrahedral framework nucleic acids (tFNAs) are a novel nano-drug delivery tool, and their good cell entry ability and stability make them an excellent carrier. Therefore, a new nanocomplex T-BBR was synthesized by carrying BBR with tFNAs. Compared with BBR, T-BBR showed better osteogenic and anti-osteoporosis abilities in both in vivo and in vitro experiments, the mechanism of which was realized through the Wnt signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease, and developing an effective treatment remains a challenge. The limited therapeutic options are primarily delivered by the oral route, among which pirfenidone (PFD) improves pulmonary dysfunction and patient quality of life. However, its high dose and severe side effects (dyspepsia and systemic photosensitivity) limit its clinical value. Intratracheal aerosolization is an excellent alternative method for treating lung diseases because it increases the concentration of the drug needed to reach the focal site. Tetrahedral framework nucleic acid (tFNA) is a drug delivery system with exceptional delivery capabilities. Therefore, we synthesized a PFD-tFNA (Pt) complex using tFNA as the delivery vehicle and achieved quantitative nebulized drug delivery to the lungs via micronebulizer for lung fibrosis treatment. In vivo , Pt exhibited excellent immunomodulatory capacity and antioxidant effects. Furthermore, Pt reduced mortality, gradually restored body weight and improved lung tissue structure. Similarly, Pt also exhibited superior fibrosis inhibition in an in vitro fibrosis model, as shown by the suppression of excessive fibroblast activation and epithelial-mesenchymal transition (EMT) in epithelial cells exposed to TGF-β1. Conclusively, Pt, a complex with tFNA as a transport system, could enrich the therapeutic regimen for IPF via intratracheal aerosolization inhalation.

Biofilm formation constitutes the primary cause of various chronic infections, such as wound infections, gastrointestinal inflammation and dental caries. While preliminary achievement of biofilm inhibition is possible, the challenge lies in the difficulty of eliminating the bactericidal effects of current drugs that lead to microbiota imbalance. This study, utilizing in vitro and in vivo models of dental caries, aims to efficiently inhibit biofilm formation without inducing bactericidal effects, even against pathogenic bacteria. The tetrahedral framework nucleic acid (tFNA) was employed as a delivery vector for a small-molecule inhibitor (smI) specifically targeting the activity of glucosyltransferases C (GtfC). It was observed that tFNA loaded smI in a small-groove binding manner, efficiently transferring it into Streptococcus mutans, thereby inhibiting GtfC activity and extracellular polymeric substances formation without compromising bacterial survival. Furthermore, smI-loaded tFNA demonstrated a reduction in the severity of dental caries in vivo without adversely affecting oral microbial diversity and exhibited desirable topical and systemic biosafety. This study emphasizes the concept of 'ecological prevention of biofilm', which is anticipated to advance the optimization of biofilm prevention strategies and the clinical application of DNA nanocarrier-based drug formulations., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the world's leading causes of blindness. The retinal pigment epithelium (RPE) and vascular endothelial cell exposed to oxidative stress is the major cause of AMD and DR. DJ-1, an important endogenous antioxidant, its overexpression is considered as a promising antioxidant treatment for AMD and DR. Here, we modified the tetrahedral frame nucleic acids (tFNAs) with DJ-1 saRNAs as a delivery system, and synthesized a novel nanocomplex (tFNAs-DJ-1 saRNAs). In vitro studies show that tFNAs-DJ-1 saRNAs can efficiently transfer DJ-1 saRNAs to human umbilical vein endothelial cells (HUVECs) and ARPE-19s, and significantly increased their cellular DJ-1 level. Reactive oxygen species expression in H 2 O 2 -treated HUVECs and ARPE-19s were decreased, cell viability was enhanced and cell apoptosis were inhibited when tFNAs-DJ-1 saRNAs were delivered. Moreover, tFNAs-DJ-1 saRNAs preserved mitochondrial structure and function under oxidative stress conditions. In the aspect of molecular mechanism, tFNAs-DJ-1 saRNAs activated Erk and Nrf2 pathway, which might contribute to its protective effects against oxidative stress damage. To conclude, this study shows the successfully establishment of a simple but effective delivery system of DJ-1 saRNAs associated with antioxidant effects in AMD and DR, which may be a promising agent for future treatment in oxidative stress-related retinal disorders., (© 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Recalcitrant staphylococcal osteomyelitis may be due, in part, to the ability of Staphylococcus aureus to invade bone cells. However, osteoclasts and osteoblasts are now recognized to shape host responses to bacterial infection and we have recently described their ability to produce IFN-β following S. aureus infection and limit intracellular bacterial survival/propagation. Here, we have investigated the ability of novel, rationally designed, nucleic acid nanoparticles (NANPs) to induce the production of immune mediators, including IFN-β, following introduction into bone cells. We demonstrate the successful delivery of representative NANPs into osteoblasts and osteoclasts via endosomal trafficking when complexed with lipid-based carriers. Their delivery was found to differentially induce immune responses according to their composition and architecture via discrete cytosolic pattern recognition receptors. Finally, the utility of this nanoparticle technology was supported by the demonstration that immunostimulatory NANPs augment IFN-β production by S. aureus infected bone cells and reduce intracellular bacterial burden., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abnormally localized nucleic acids (NAs) are considered as pathogen associated molecular patterns (PAMPs) in innate immunity. They are recognized by NAs-specific pattern recognition receptors (PRRs), leading to the activation of associated signaling pathways and subsequent production of type I interferons (IFNs) and pro-inflammatory cytokines, which further trigger the adaptive immunity. Notably, NAs-mediated innate immune activation is highly dependent on the conformation changes, especially the aggregation of PRRs. Evidence indicates that the characteristics of NAs including their length, concentration and even spatial structure play essential roles in inducing the aggregation of PRRs. Therefore, nucleic acid materials (NAMs) with high valency of NAs and high-order structures hold great potential for activating innate and adaptive immunity, making them promising candidates for cancer immunotherapy. In recent years, a variety of NAMs have been developed and have demonstrated significant efficacy in achieving satisfactory anti-tumor immunity in multiple mouse models, exhibiting huge potential for clinical application in cancer treatment. This review aims to discuss the mechanisms of NAMs-mediated innate immune response, and summarize their applications in cancer immunotherapy., (© 2024 Wiley-VCH GmbH.)

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., (© 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Bacterial resistance and excessive inflammation are common issues that hinder wound healing. Antimicrobial peptides (AMPs) offer a promising and versatile antibacterial option compared to traditional antibiotics, with additional anti-inflammatory properties. However, the applications of AMPs are limited by their antimicrobial effects and stability against bacterial degradation. TFNAs are regarded as a promising drug delivery platform that could enhance the antibacterial properties and stability of nanodrugs. Therefore, in this study, a composite hydrogel (HAMA/t-GL13K) was prepared via the photocross-linking method, in which tFNAs carry GL13K. The hydrogel was injectable, biocompatible, and could be instantly photocured. It exhibited broad-spectrum antibacterial and anti-inflammatory properties by inhibiting the expression of inflammatory factors and scavenging ROS. Thereby, the hydrogel inhibited bacterial infection, shortened the wound healing time of skin defects in infected skin full-thickness defect wound models and reduced scarring. The constructed HAMA/tFNA-AMPs hydrogels exhibit the potential for clinical use in treating microbial infections and promoting wound healing., (© 2024. The Author(s).)

Use of small molecules as valuable drugs against diseases is still an indefinable purpose due to the lack of in-detail knowledge regarding proper bio-target identification, specificity aspects, mode-mechanism of binding and proper in vitro study. Harmaline, an important beta-carboline alkaloid, shows effective anti-proliferative action against different types of human cancers and is also found to be a nucleic acid targeting natural molecule. This review sought to address the different signal pathways of apoptosis by harmaline in different cancer cell lines and simultaneously to characterize the structure activity aspects of the alkaloid with different motifs of nucleic acid to show its preference, biological efficacy and genotoxicity. The results open up new insights for the design and development of small molecule-based nucleic acid therapeutic agents.

Uropathogenic Escherichia coli (UPEC) is the primary causative agent of lower urinary tract infection (UTI). UTI presents a serious health risk and has considerable secondary implications including economic burden, recurring episodes, and overuse of antibiotics. A safe and effective vaccine would address this widespread health problem and emerging antibiotic resistance. Killed, whole-cell vaccines have shown limited efficacy to prevent recurrent UTI in human trials. We explored photochemical inactivation with psoralen drugs and UVA light (PUVA), which crosslinks nucleic acid, as an alternative to protein-damaging methods of inactivation to improve whole-cell UTI vaccines. Exposure of UPEC to the psoralen drug AMT and UVA light resulted in a killed but metabolically active (KBMA) state, as reported previously for other PUVA-inactivated bacteria. The immunogenicity of PUVA-UPEC as compared to formalin-inactivated UPEC was compared in mice. Both generated high UPEC-specific serum IgG titers after intramuscular delivery. However, using functional adherence as a measure of surface protein integrity, we found differences in the properties of PUVA- and formalin-inactivated UPEC. Adhesion mediated by Type-1 and P-fimbriae was severely compromised by formalin but was unaffected by PUVA, indicating that PUVA preserved the functional conformation of fimbrial proteins, which are targets of protective immune responses. In vitro assays indicated that although they retained metabolic activity, PUVA-UPEC lost virulence properties that could negatively impact vaccine safety. Our results imply the potential for PUVA to improve killed, whole-cell UTI vaccines by generating bacteria that more closely resemble their live, infectious counterparts relative to vaccines generated with protein-damaging methods., Importance: Lower urinary tract infection (UTI), caused primarily by uropathogenic Escherichia coli , represents a significant health burden, accounting for 7 million primary care and 1 million emergency room visits annually in the United States. Women and the elderly are especially susceptible and recurrent infection (rUTI) is common in those populations. Lower UTI can lead to life-threatening systemic infection. UTI burden is manifested by healthcare dollars spent (1.5 billion annually), quality of life impact, and resistant strains emerging from antibiotic overuse. A safe and effective vaccine to prevent rUTI would address a substantial healthcare issue. Vaccines comprised of inactivated uropathogenic bacteria have yielded encouraging results in clinical trials but improvements that enhance vaccine performance are needed. To that end, we focused on inactivation methodology and provided data to support photochemical inactivation, which targets nucleic acid, as a promising alternative to conventional protein-damaging inactivation methods to improve whole-cell UTI vaccines., Competing Interests: The authors declare no conflict of interest.

Ankylosing spondylitis (AS) is a chronic systemic inflammatory disease that leads to serious spinal deformity and ankylosis. Persistent inflammation and progressive ankylosis lead to loss of spinal flexibility in patients with AS. Tetrahedral framework nucleic acids (tFNAs) have emerged as a one kind of nanomaterial composed of four specially designed complementary DNA single strands with outstanding biological properties. Results from in vivo experiments demonstrated that tFNAs treatment could inhibit inflammatory responses and heterotopic ossification to halt disease progression. In vitro , tFNAs were proved to influence the biological behavior of AS primary chondrocytes and inhibit the secretion of pro-inflammatory cytokines through interleukin-17 pathway. The osteogenic process of chondrocytes was as well inhibited at the transcriptional level to regulate the expression of related proteins. Therefore, we believe tFNAs had a strong therapeutic effect and could serve as a nonsurgical remedy in the future to help patients suffering from AS.

In vertebrates, enzymes responsible for DNA methylation, one of the epigenetic mechanisms, are encoded by genes falling into the cytosine methyltransferases genes family (Dnmt1, Dnmt3a,b and Dnmt3L). However, in Diptera, only the methyltransferase Dnmt2 was found, suggesting that DNA methylation might act differently for species in this order. Moreover, genes involved in epigenetic dynamics, such as Ten-eleven Translocation dioxygenases (TET) and Methyl-CpG-binding domain (MBDs), present in vertebrates, might play a role in insects. This work aimed at investigating nucleic acids methylation in the malaria vector Anopheles gambiae (Diptera: Culicidae) by analysing the expression of Dnmt2, TET2 and MBDs genes using quantitative real-time polymerase chain reaction (qRT-PCR) at pre-immature stages and in reproductive tissues of adult mosquitoes. In addition, the effect of two DNA methylation inhibitors on larval survival was evaluated. The qPCR results showed an overall low expression of Dnmt2 at all developmental stages and in adult reproductive tissues. In contrast, MBD and TET2 showed an overall higher expression. In adult mosquito reproductive tissues, the expression level of the three genes in males' testes was significantly higher than that in females' ovaries. The chemical treatments did not affect larval survival. The findings suggest that mechanisms other than DNA methylation underlie epigenetic regulation in An. gambiae., (© 2023 Royal Entomological Society.)

Currently approved treatment of patients with chronic hepatitis B infection is insufficient to achieve functional cure. Numerous new compounds are identified, and among many, capsid assembly modulators (CAMs) and nucleic acid polymers (NAPs) are 2 classes of virus-directing agents in clinical development. CAMs interfere with viral pregenomic RNA encapsidation and are effective in viral load reduction but have limited effects on hepatitis B surface antigen (HBsAg). NAPs prevent HBsAg release from hepatocytes and induce intracellular degradation, leading to potent suppression of serum HBsAg when combined with nucleoside analogues and pegylated interferon demonstrated by initial data, but awaiting further confirmation studies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Macrophages' activation plays a central role during the development and progression of inflammation, while the regulation of metabolic reprogramming of macrophages has been recently identified as a novel strategy for anti-inflammatory therapies. Our previous studies have found that tetrahedral framework nucleic acid (tFNA) plays a mild anti-inflammatory effect by inhibiting macrophage activation, but the specific mechanism remains unclear. Here, by metabolomics and RNA sequencing, choline uptake is identified to be significantly repressed by decreased slc44a1 expression in tFNA-treated activated macrophages. Inspired by this result, combined with the excellent delivery capacities of tFNA, siR-slc44a1 is loaded into the tFNA to develop a new tFNA-based small interfering RNA (siRNA) delivery system named 'nano-windmill,' which exhibits a synergetic role by targeting slc44a1, finally blowing up the anti-inflammatory effects of tFNA to inhibit macrophages activation via reducing choline uptake. By confirming its anti-inflammatory effects in chronic (periodontitis) and acute (sepsis) inflammatory disease, the tFNA-based nanomedicine developed for inflammatory diseases may provide broad prospects for tFNA upgrading and various biological applications such as anti-inflammatory., (© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

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.)

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., (© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Senile osteoporotic fracture has aroused increasing attention due to high morbidity and mortality. However, to date, there is no effective therapeutic approach available. Senile osteoporosis is characterized by impaired osteogenesis and angiogenesis, osteoporotic fracture repair could also be promoted by enhancing osteogenesis and angiogenesis. Tetrahedral framework nucleic acids (tFNAs) are a multifunctional nanomaterial that have recently been extensively used in biomedical fields, which could enhance osteogenesis and angiogenesis in vitro. Therefore, we applied tFNAs to intact and femoral fractural senile osteoporotic mice, respectively, to evaluate the effects of tFNAs on senile osteoporosis and osteoporotic fracture repair regarding the osteogenesis and angiogenesis of the callus at the early healing stages and to initially explore the potential mechanism. The outcomes showed that tFNAs had no significant effects on the osteogenesis and angiogenesis of the femur and mandible in intact senile osteoporotic mice within 3 weeks after tFNA treatment, while tFNAs could promote osteogenesis and angiogenesis of callus in osteoporotic fracture repair, which may be regulated by a FoxO1-related SIRT1 pathway. In conclusion, tFNAs could promote senile osteoporotic fracture repair by enhancing osteogenesis and angiogenesis, offering a new strategy for the treatment of senile osteoporotic fracture.

Acute kidney injury (AKI) is not only a worldwide problem with a cruel hospital mortality rate but also an independent risk factor for chronic kidney disease and a promoting factor for its progression. Despite supportive therapeutic measures, there is no effective treatment for AKI. This study employs tetrahedral framework nucleic acid (tFNA) as a vehicle and combines typhaneoside (Typ) to develop the tFNA-Typ complex (TTC) for treating AKI. With the precise targeting ability on mitochondria and renal tubule, increased antiapoptotic and antioxidative effect, and promoted mitochondria and kidney function restoration, the TTC represents a promising nanomedicine for AKI treatment. Overall, this study has developed a dual-targeted nanoparticle with enhanced therapeutic effects on AKI and could have critical clinical applications in the future.

Lysozyme can kill bacteria by its enzymatic activity or through a mechanism involving its cationic nature, which can facilitate electrostatic interactions with the viral capsid, the negatively charged parts of nucleic acids, and polymerase, so binding to nucleic acids may be another biological function of lysozyme. Here, PCR was used as a research tool to detect the effects of lysozyme on the replication and transcription of nucleic acids after treatment in different ways. We found that lysozyme and its hydrolysate can enter cells and inhibit PCR to varying degrees in vitro, and degraded lysozyme inhibited nucleic acid replication more effectively than intact lysozyme. The inhibition of lysozyme may be related to polymerase binding, and the sensitivity of different polymerases to lysozyme is inconsistent. Our findings provide a theoretical basis for further explaining the pharmacological effects of lysozyme, such as antibacterial, antiviral, anticancer, and immune regulatory activities, and directions for the development of new pharmacological effects of lysozyme and its metabolites., (© 2023. The Author(s).)

In this study, we investigated the role of tetrahedral framework nucleic acids (tFNAs) in irradiation-induced salivary gland damage in vitro and in vivo. Irradiation-damaged submandibular gland cells (SMGCs) were treated with different concentrations of tFNAs. Cell activity was measured by CCK-8 assay. Cell death was detected by Calcein-AM/PI double staining. Cell apoptosis was assessed by flow cytometry. The expression of apoptosis proteins and inflammatory cytokines were detected by western blot. Body weight, drinking volume, saliva flow rate and lag time was measured 8 weeks after irradiation. Micromorphological changes of submandibular gland were assessed by haematoxylin-eosin and masson staining. Cell proliferation, apoptosis and microvessel density of submandibular gland were evaluated by immunohistochemical staining. tFNAs could promote cell proliferation, inhibit cell apoptosis of irradiation-damaged SMGCs and reduce irradiation induced cell death. Mechanism studies revealed that tFNAs inhibited cell apoptosis through regulating the Bcl-2/Bax/Caspase-3 signalling pathway and inhibited the release of TNF-α, IL-1β and IL-6 to reduce cell damage caused by inflammation. Animal experiments showed that tFNAs could alleviate irradiation-induced weight loss, increased water intake, decreased saliva production and prolonged salivation lag time and could ameliorate salivary gland damage. tFNAs have a positive effect on alleviating irradiation-induced salivary gland damage and might be a promising agent for the treatment of this disease., (© 2022 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

The sterilizing effect of a combination of heat (80, 90, and 100 °C) and ε-polylysine (ε-PL, 0.25 and 1 g/L) treatments on Bacillus subtilis spores was investigated and compared with that of conventional heat sterilization. The inactivation rate of spores and changes in their protective structure were evaluated using different methods and techniques. Changes in cell membrane's fatty acids, cell walls, proteins and nucleic acids were also analyzed. The results showed that the combined heat and ε-PL treatments significantly (p < 0.05) inactivated the Bacillus subtilis spores compared with the single heat treatment. Besides, the inactivation of spores was enhanced as the temperature and ε-PL concentration of combined treatments increased. The inactivation rate was found to be 2.18 log after heating at 90 °C for 60 min combined with the addition of 1 g/L ε-PL. Additionally, the electrical conductivity of spores' suspension and the positive region of flow cytometry significantly (p < 0.05) increased depending on temperature and ε-PL concentration of a combination treatment, indicating significant damage in the cell membranes and increased permeability. Significant changes in the spore morphology were also observed by the microscopy analysis after a combination treatment. Furthermore, the Fourier transform infrared spectra indicated a phase change in the inner membrane and alteration in the structure of peptidoglycan layer, as well as protein and nucleic acids denaturation after combined treatments. Therefore, the combined heat and ε-PL treatments can be suggested as sterilizing alternative to conventional heat sterilization in the food industry., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To determine the therapeutic effect of tetrahedral framework nucleic acids (tFNAs) on diabetic wound healing and the underlying mechanism., Materials and Methods: The tFNAs were characterized by polyacrylamide gel electrophoresis (PAGE), atomic force microscopy (AFM), transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential assays. Cell Counting Kit-8 (CCK-8) and migration assays were performed to evaluate the effects of tFNAs on cellular proliferation and migration. Quantitative polymerase chain reaction (Q-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the effect of tFNAs on growth factors. The function and role of tFNAs in diabetic wound healing were investigated using diabetic wound models, histological analyses and western blotting., Results: Cellular proliferation and migration were enhanced after treatment with tFNAs in a high-glucose environment. The expression of growth factors was also facilitated by tFNAs in vitro. During in vivo experiments, tFNAs accelerated the healing process in diabetic wounds and promoted the regeneration of the epidermis, capillaries and collagen. Moreover, tFNAs increased the secretion of growth factors and activated the Wnt pathway in diabetic wounds., Conclusions: This study indicates that tFNAs can accelerate diabetic wound healing and have potential for the treatment of diabetic wounds., (© 2022 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

The knowledge about amino acid metabolism in trypanosomatids is a valuable source of new therapeutic targets. l-arginine is an essential amino acid for Leishmania parasites, and it participates in the synthesis of polyamines, a group of essential nutrients used for nucleic acids, proteins biosynthesis, and redox modulation necessary for proliferation. In the present study, we evaluated the effect of changes in the availability of this amino acid on promastigotes and intracellular amastigotes on U937 macrophages and showed that the absence of l-arginine in culture medium negatively influences the growth and infectivity of Leishmania (Viannia) braziliensis, causing a decrease in the percentage of the infected cells and parasite load tested through light microscopy. In addition, the absence of l-arginine resulted in the parasite's inability to regulate its reactive oxygen species (ROS) production, which persisted for up to 24 h by flow cytometry following the probe H2DCF-DA dye. Moreover, the differentiation of promastigote to amastigote in axenic culture was more significant at low concentrations of l-arginine suggesting that this depletion induces a stress environment to increase this transformation under axenic conditions. No association was established between the availability of l-arginine and the effectiveness of antileishmanial drugs. All these results confirm the importance of l-arginine in L. braziliensis life cycle vital processes, such as its replication and infectivity, as documented in other Leishmania species. Based on these results, we proposed that the l-arginine uptake/metabolism route is possible in exploring new antileishmanial drugs., Competing Interests: Declaration of competing interest No conflict of interest is declared., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Current medications used to treat alcoholic liver injury (ALD) can cause secondary damage to the liver. Therefore, it is important to improve alcoholic liver injury from the perspective of dietary and nutritional supplementation. Nucleic acids, as functional biomolecules, are present in almost all foods, especially in aquatic products, but their edible research has been neglected for a long time. Hence, the effects of a typical aquatic nucleic acid, namely, salmon sperm DNA, in acute, and chronic alcoholic liver injury model of male ICR mice were studied. The results showed that salmon sperm DNA significantly attenuated the accumulation of cholesterol (TC) and triglycerides (TG) in acute alcoholic liver injury, and it was further demonstrated to mainly regulate lipid metabolism by fluorescent quantitative PCR and immunoblotting experiments. In addition, nucleic acid intervention alleviated inflammation and apoptosis in mice with chronic alcoholic liver injury. PRACTICAL APPLICATIONS: These results suggest that salmon sperm DNA can prevent and ameliorate alcoholic liver injury and can be used as an effective dietary and nutritional supplement for the prevention and treatment of ALD. Moreover, this study provided some new ideas for the development and utilization of large aquatic nucleic acid resources, promoted the comprehensive use of fish processing waste, such as fish sperm, and provided new directions for reducing emissions., (© 2022 Wiley Periodicals LLC.)

Background: The widespread use of antibiotics has led to the emergence of many drug-resistant strains; thus, the development of new antibacterial drugs is essential with antimicrobial peptides becoming the focus of research. This study assessed the antibacterial effect of a novel antimicrobial peptide, named LL-1 on Escherichia coli (E.coli) by determining the minimum inhibitory concentration (MIC) and the antibacterial curve. The interaction between LL-1 and E. coli DNA was then detected by nucleic acid gel electrophoresis. The effect of LL-1 on the E. coli cell membrane was assessed by detecting the leakage of β-galactosidase, nucleic acid and protein. The influence of LL-1 on the intracellular ATP of E. coli was analysed by determining the concentration of intracellular ATP. Finally, the bacteria and colonies of E. coli treated with LL-1 were observed using scanning and transmission electron microscopy., Results: The results suggested that the MIC value was 3.125 µg/ml, and the antibacterial effect was dose-dependent. LL-1 dose-dependently combined with E. coli DNA. LL-1 resulted in the leakage of intracellular β-galactosidase, nucleic acid and protein, and decreased intracellular ATP concentrations of E. coli. Two MIC of LL-1 caused E. coli to shrink, resulting in a rough surface, plasmolysis, and bacterial adhesion., Conclusion: This study indicated that LL-1 had a good bactericidal effect on E. coli by mainly increasing the permeability of the cell membrane, leading to leakage of the intracellular content. This will lay the foundation for an in-depth study on the antibacterial mechanism of LL-1 against E. coli and its clinical application., (© 2022. The Author(s).)

Objectives: Peptide-based therapeutics are natural candidates to desirable wound healing. However, enzymatic surroundings largely limit its stability and bioavailability. Here, we developed a tetrahedral framework nucleic acids(tFNA)-based peptide delivery system, that is, p@tFNAs, to address deficiencies of healing peptide stability and intracellular delivery in diabetic wound healing., Materials and Methods: AGEs (advanced glycation end products) were used to treat endothelial cell to simulate cell injury in diabetic microenvironment. The effects and related mechanisms of p@tFNAs on endothelial cell proliferation, migration, angiogenesis and ROS (reactive oxygen species) production have been comprehensively studied. The wound healing model in diabetic mice was photographically and histologically investigated in vivo., Results: Efficient delivery of healing peptide by the framework(tFNA) was verified. p@tFNAs helped overcome the angiogenic obstacles induced by AGEs via ERK1/2 phosphorylation. In the meantime, p@tFNA exhibited its antioxidative property to achieve ROS balance. As a result, p@tFNA improved angiogenesis and diabetic wound healing in vitro and in vivo., Conclusions: Our findings demonstrate that p@tFNA could be a novel therapeutic strategy for diabetic wound healing. Moreover, a new method for intracellular delivery of peptides was also constructed., (© 2022 The Authors. Cell Proliferation published by European Cell Proliferation Society and John Wiley & Sons Ltd.)

Astrocytes, as the most plentiful subtypes of glial cells, play an essential biphasic function in ischemic stroke (IS). However, although having beneficial effects on stroke via promoting nerve restoration and limiting lesion extension, astrocytes can unavoidably cause exacerbated brain damage due to their participation in the inflammatory response. Therefore, seeking an effective and safe drug/strategy for protecting and regulating astrocytes in stroke is urgent. Here, we employ tetrahedral framework nucleic acid (tFNA) nanomaterials for astrocytes in stroke, considering their excellent biological properties and outstanding biosafety. In vitro, tFNA can inhibit calcium overload and ROS regeneration triggered by oxygen-glucose deprivation/reoxygenation (OGD/R), which provides a protective effect against astrocytic apoptosis. Furthermore, morphological changes such as hyperplasia and hypertrophy of reactive astrocytes are restrained, and the astrocytic polarization from the proinflammatory A1 phenotype to the neuroprotective A2 phenotype is facilitated by tFNA, which further alleviates cerebral infarct volume and facilitates the recovery of neurological function in transient middle cerebral artery occlusion (tMCAo) rat models. Moreover, the TLRs/NF-κB signaling pathway is downregulated by tFNA, which may be the potential mechanism of tFNA for protecting astrocytes in stroke. Collectively, we demonstrate that tFNA can effectively mediate astrocytic apoptosis, activation, and polarization to alleviate brain injury, which represents a potential intervention strategy for IS.

The repair of damaged endothelium is crucial for vascular homeostasis maintenance, which comprises the recovery of early stage impaired endothelial cells and migration of surrounding unimpaired endothelial cells. MicroRNAs (miRNAs) play an indispensable role in balancing gene expression in organisms. For vascular tissues, miR-126 is one of the most important regulators and might have substantial application potential in maintaining vascular homeostasis. In this study, a type of sticky-end-modified tetrahedral framework nucleic acids (tFNAs-SE) was employed to successfully link the miR-126 5p mimic duplex, which was termed tFNAs-miR-126 5p mimics (tFNAs-MMs). Existing vascular endothelial growth factors (VEGF), tFNAs-MMs can improve cell viability, resist apoptosis, and recover the state and functions of LPS-induced impaired human umbilical vein endothelial cells (HUVECs). The angiogenesis ability of impaired HUVECs was recovered by tFNAs-MMs in vitro and in vivo . The mechanisms underlying these phenomena were demonstrated to be related to the downregulation of caspase3 and negative regulators of VEGF (SPRED1 and PIK3R2). Moreover, tFNAs-MMs promoted the migration and proliferation of HUVECs. Briefly, the strategy of sticky-end-modified tFNAs connecting miRNA mimics is available for miRNA gain of function, while tFNAs-MMs might be a promising agent for repairing early stage vascular damage and maintaining vascular homeostasis.

Objectives: The purpose of this study was to investigate the treatment effect and molecular mechanism of tetrahedral framework nucleic acids (tFNAs), novel self-assembled nucleic acid nanomaterials, in diffuse BMEC injury after SAH., Materials and Methods: tFNAs were synthesized from four ssDNAs. The effects of tFNAs on SAH-induced diffuse BMEC injury were explored by a cytotoxicity model induced by hemin, a breakdown product of hemoglobin, in vitro and a mouse model of SAH via internal carotid artery puncture in vivo. Cell viability assays, wound healing assays, transwell assays, and tube formation assays were performed to explore cellular function like angiogenesis., Results: In vitro cellular function assays demonstrated that tFNAs could alleviate hemin-induced injury, promote angiogenesis, and inhibit apoptosis in hemin cytotoxicity model. In vivo study using H&E and TEM results jointly indicated that the tFNAs attenuate the damage caused by SAH in situ, showing restored number of BMECs in the endothelium layer and more tight intercellular connectivity. Histological examination of SAH model animals confirmed the results of the in vitro study, as tFNAs exhibited treatment effects against diffuse BMEC injury in the cerebral microvascular bed., Conclusions: Our study suggests the potential of tFNAs in ameliorating diffuse injury to BMECs after SAH, which laid theoretical foundation for the further study and use of these nucleic acid nanomaterials for tissue engineering vascularization., (© 2022 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.)

More than 15 million out of 70 million patients worldwide do not respond to available antiepilepticus drugs (AEDs). With the emergence of nanomedicine, nanomaterials are increasingly being used to treat many diseases. Here, we report that tetrahedral framework nucleic acid (tFNA), an assembled nucleic acid nanoparticle, showed an excellent ability to the cross blood-brain barrier (BBB) to inhibit M1 microglial activation and A1 reactive astrogliosis in the hippocampus of mice after status epilepticus. Furthermore, tFNA inhibited the downregulation of glutamine synthetase by alleviating oxidative stress in reactive astrocytes and subsequently reduced glutamate accumulation and glutamate-mediated neuronal hyperexcitability. Meanwhile, tFNA promotes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization in the postsynaptic membrane by regulating AMPAR endocytosis, which contributed to reduced calcium influx and ultimately reduced hyperexcitability and spontaneous epilepticus spike frequencies. These findings demonstrated tFNA as a potential AED and that nucleic acid material may be a new direction for the treatment of epilepsy.

Liver failure is a serious disease that is characterized by global hepatocyte necrosis. Hepatocyte proliferation and liver regeneration are critically important for the success of treatments for liver disease. Tetrahedral framework nucleic acids (TFNAs), which are widely used antioxidants and anti-inflammatory nanomaterials, activate multiple proliferation and prosurvival pathways. Therefore, the effects of a TFNA on hepatocyte proliferation and liver regeneration in mouse livers injured by 70% partial hepatectomy (PHx), acetaminophen overdose, and carbon tetrachloride were explored in this study. The TFNA, which was successfully self-assembled from four specifically designed ssDNAs, entered the body quickly and was taken up effectively by hepatocytes in the liver and could eventually be cleared by the kidneys. The TFNA promoted hepatocyte proliferation in vitro by activating the Notch and Wnt signaling pathways. In the three in vivo mouse models of liver injury, the TFNA attenuated the injuries and enhanced liver regeneration by regulating the cell cycle and the P53 signaling pathway. Therefore, by promoting hepatocyte proliferation and enhancing liver regeneration, the TFNA shows potential as an effective therapeutic agent for treating acute liver injury induced by 70% PHx and other factors, thereby preventing the progression to acute liver failure and reducing the associated mortality rate.

Over-expression of the vesicular stomatitis virus glycoprotein (VSVG) in mammalian cells can induce the formation of VSVG-pseudotyped vesicles (named "gesicles") from membrane budding. Its use as a nucleic acid delivery tool is still poorly documented. Naked-plasmid DNA can be delivered in animal cells with gesicles in presence of hexadimethrine bromide (polybrene). However, little is known about gesicle manufacturing process and conditions to obtain successful nucleic acid delivery. In this study, gesicles production process using polyethylenimine (PEI)-transfected HEK293 cells was developed by defining the VSVG-plasmid concentration, the DNA:PEI mass ratio, and the time of gesicle harvest. Furthermore, parameters described in the literature relevant for nucleic acid delivery such as (i) component concentrations in assembly mixture, (ii) component addition order, (iii) incubation time, and (iv) polybrene concentration were tested by assessing the transfection capacity of the gesicles complexed with a green fluorescent protein (GFP)-coding plasmid. Interestingly, freezing/thawing cycles and storage at + 4 °C, - 20 °C, and - 80 °C did not reduce gesicles' ability to transfer plasmid DNA. Transfection efficiency of 55% and 22% was obtained for HeLa cells and for hard-to-transfect cells such as human myoblasts, respectively. For the first time, gesicles were used for delivery of a large plasmid (18-kb) with 42% of efficiency and for enhanced green fluorescent protein (eGFP) gene silencing with siRNA (up to 60%). In conclusion, gesicles represent attractive bioreagents with great potential to deliver nucleic acids in mammalian cells., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nucleic acid-mediated interferon signaling plays a pivotal role in defense against microorganisms, especially during viral infection. Receptors sensing exogenous nucleic acid molecules are localized in the cytosol and endosomes. Cytosolic sensors, including cGAS, RIG-I, and MDA5, and endosome-anchored receptors are toll-like receptors (TLR3, TLR7, TLR8, and TLR9). These TLRs share the same domain architecture and have similar structures, facing the interior of endosomes so their binding to nucleic acids of invading pathogens via endocytosis is possible. The correct function of these receptors is crucial for cell homeostasis and effective response against pathogen invasion. A variety of endogenous mechanisms modulates their activities. Nevertheless, naturally occurring mutations lead to aberrant TLR-mediated interferon (IFN) signaling. Furthermore, certain pathogens require a more robust defense against control. Thus, manipulating these TLR activities has a profound impact. High-throughput virtual screening followed by experimental validation led to the discovery of numerous chemicals that can change these TLR-mediated IFN signaling activities. Many of them are unique in selectivity, while others regulate more than one TLR due to commonalities in these receptors. We summarized these nucleic acid-sensing TLR-mediated IFN signaling pathways and the corresponding chemicals activating or deactivating their signaling., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Human Immunodeficiency Virus (HIV) infection continues to be a significant health burden in many countries around the world. Current HIV treatment through a combination of different antiretroviral drugs (cART) effectively suppresses viral replication, but drug resistance and crossresistance are significant challenges. This has prompted the search for novel targets and agents, such as nucleic acid aptamers. Nucleic acid aptamers are oligonucleotides that attach to the target sites with high affinity and specificity. This review provides a target-by-target account of research into anti-HIV aptamers and summarises the challenges and prospects of this therapeutic strategy, specifically in the unique context of HIV infection., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Herpes zoster (HZ) remains a significant health burden with millions of cases in North America and Europe annually. HZ is frequently followed by long-term pain or post-herpetic neuralgia (PHN). Although effective vaccines for HZ are available, currently used nucleotide analogues often have limited effectiveness against HZ and especially PHN, so there remains a need for additional antiviral therapies for HZ. We recently identified a population of small non-coding RNA (sncRNA) encoded by Varicella Zoster Virus (VZV) and showed that single locked-nucleic acid antagonists (LNAA) to some sncRNA can modulate VZV replication in cell culture. In this work, we explored the antiviral effects of combinations of LNAA oligonucleotides targeting VZVsncRNA. Combinations of LNAA targeting three VZVsncRNA encoded in and near a critical viral regulatory gene were additive, achieving 96 % reduction in virus growth in a cell line. VZV growth was also inhibited by more than 90 % in primary human skin fibroblast cultures by individual and combinations of LNAA to VZVsncRNA. The inhibition by VZVsncRNA was specific and not a consequence of innate immune responses since LNAA to a different VZVsncRNA enhanced VZV growth. Targeted VZVsncRNA lack homologous sequences in the human transcriptome suggesting that LNAA to them would have reduced cytotoxicity if used as therapeutics. These results support further development of oligonucleotides targeting VZVsncRNA as a novel treatment for HZ., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Spontaneous formation of protein corona on chitosan-based nano-carriers is inevitable once they enter the blood, which is considered to be an important factor that weakens the delivery efficiency and therapeutic effect of nucleic acid drugs. For this, cyclic RGDyK peptide (cRGD) modified bovine serum albumin (BSA) was designed as a corona to precoat on redox-responsive chitosan-based nano-carriers (TsR NPs) before administration. The effects of the precoating corona on the pharmaceutical properties and delivery efficiency of the nano-carriers and the therapeutic effect of model siRNA (siVEGF) were investigated. The results showed that BSA-cRGD formed steady corona around TsR NPs, which enhanced targeting ability to cancer cells and reduced serum proteins adsorption. The Bc corona improved the stability and biocompatibility of TsR NPs, increased the intracellular uptake, facilitated the lysosomal escape and maintained their redox-sensitive responsiveness, resulting in enhanced gene silencing efficiency and anti-tumor proliferation effects both in vitro and in vivo., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Autoimmune diseases are a heterogeneous group of diseases which lose the immunological tolerance to self-antigens. It is well recognized that irregularly provoked T cells participate in the pathological immune responses. As a novel nanomaterial with promising applications, tetrahedral framework nucleic acid (TFNA) nanostructure was found to have immune regulatory effects on T cells in this study., Materials and Methods: To verify the successful fabrication of TFNA, the morphology of TFNA was observed by atomic force microscopy (AFM) and dynamic light scattering. The regulatory effect of TFNA was evaluated by flow cytometry after cocultured with CD3+ T cells isolated from healthy donors. Moreover, the associated signaling pathways were investigated. Finally, we verified our results on the T cells from patients with neuromyelitis optica spectrum disorder (NMOSD), which is a typical autoimmune disease induced by T cells., Results: We revealed the alternative regulatory functions of TFNA in human primary T cells with steady status via the JNK signaling pathway. Moreover, by inhibiting both JNK and ERK phosphorylation, TFNA exhibited significant suppressive effects on IFNγ secretion from provoking T cells without affecting TNF secretion. Similar immune regulatory effects of TFNA were also observed in autoreactive T cells from patients with NMOSD., Conclusions: Overall, our results revealed a potential application of TFNA in regulating the adaptive immune system, as well as shed a light on the treatment of T cell-mediated autoimmune diseases., (© 2021 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.)

Radiation induces the generation of platelet-activating factor receptor (PAF-R) ligands, including PAF and oxidized phospholipids. Alternatively, PAF is also synthesized by the biosynthetic enzymes lysophosphatidylcholine acyltransferases (LPCATs) which are expressed by tumor cells including melanoma. The activation of PAF-R by PAF and oxidized lipids triggers a survival response protecting tumor cells from radiation-induced cell death, suggesting the involvement of the PAF/PAF-R axis in radioresistance. Here, we investigated the role of LPCATs in the melanoma cell radiotherapy response. LPCAT is a family of four enzymes, LPCAT1-4, and modular nucleic acid nanoparticles (NANPs) allowed for the simultaneous silencing of all four LPCATs. We found that the in vitro simultaneous silencing of all four LPCAT transcripts by NANPs enhanced the therapeutic effects of radiation in melanoma cells by increasing cell death, reducing long-term cell survival, and activating apoptosis. Thus, we propose that NANPs are an effective strategy for improving radiotherapy efficacy in melanomas., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In a search for a solution to large-area soft and hard tissue defects, whether or not tissue regeneration or tissue-substitutes transplantation is used, the problems with angiogenesis need to be solved urgently. Thus, a new and efficient proangiogenic approach is needed. Nanoengineering systems have been considered one of the most promising approaches. In this study, we modify the tetrahedral framework nucleic acid (tFNA) for the first time with two different angiogenic DNA aptamers to form aptamer-tFNA nanostructures, tFNA-Apt02 and tFNA-AptVEGF, and the effects of them on angiogenesis both in vitro and in vivo are investigated. We develop new nanomaterials for enhancing angiogenesis to solve the problem of tissue engineering vascularization and ischemic diseases. The results of our study confirm that tFNA-Apt02 and tFNA-AptVEGF has a stronger ability to accelerate endothelial cell proliferation and migration, tubule formation, spheroid sprouting, and angiogenesis in vivo. We first demonstrate that the engineered novel tFNA-Apt02 and tFNA-AptVEGF have promoting effects on angiogenesis both in vitro and in vivo and provide a theoretical basis and opportunity for their application in tissues engineering vascularization and ischemic diseases.

The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. Their clinical translation, however, depends on delivery technologies that improve stability, facilitate internalization and increase target affinity. Here, we review four platform technologies that have enabled the clinical translation of nucleic acid therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles and adeno-associated virus vectors. For each platform, we discuss the current state-of-the-art clinical approaches, explain the rationale behind its development, highlight technological aspects that facilitated clinical translation and provide an example of a clinically relevant genetic drug. In addition, we discuss how these technologies enable the development of cutting-edge genetic drugs, such as tissue-specific nucleic acid bioconjugates, messenger RNA and gene-editing therapeutics.

Melanoma accounts for 4% of all skin cancer malignancies, with only 14% of diagnosed patients surviving for more than 5 years after diagnosis. Until now, there is no clear understanding of the detailed molecular contributors of melanoma pathogenesis. Accordingly, more research is needed to understand melanoma development and prognosis.All the treatment approaches that are currently applied have several significant limitations that prevent effective use in melanoma. One major limitation in the treatment of cancer is the acquisition of multidrug resistance (MDR). The MDR results in significant treatment failure and poor clinical outcomes in several cancers, including skin cancer. Treatment of melanoma is especially retarded by MDR. Despite the current advances in targeted and immune-mediated therapy, treatment arms of melanoma are severely limited and stand as a significant clinical challenge. Further, the poor pharmacokinetic profile of currently used chemotherapeutic agents is another reason for treatment failure. Therefore, more research is needed to develop novel drugs and carrier tools for more effective and targeted treatment.Nucleic acid therapy is based on nucleic acids or chemical compounds that are closely related, such as antisense oligonucleotides, aptamers, and small-interfering RNAs that are usually used in situations when a specific gene implicated in a disorder is deemed a therapeutically beneficial target for inhibition. However, the proper application for nucleic acid therapies is hampered by the development of an effective delivery system that can maintain their stability in the systemic circulation and enhance their uptake by the target cells. In this chapter, the prognosis of the different types of melanoma along with the currently used medications is highlighted, and the different types of nucleic acids along with the currently available nanoparticle systems for delivering these nucleic acids into melanoma cells are discussed. We also discuss recently conducted research on the use of different types of nanoparticles for nucleic acid delivery into melanoma cells and highlight the most significant outcomes.

Due to the misuse of antibiotics, multiple drug-resistant pathogenic bacteria have increasingly emerged. This has increased the difficulty of treatment as these bacteria directly affect public health by diminishing the potency of existing antibiotics. Developing alternative therapeutic strategies is the urgent need to reduce the mortality and morbidity related to drug-resistant bacterial infections. In the past 10 to 20 years, nanomedicines have been widely studied and applied as an antibacterial agent. They have become a novel tool for fighting resistant bacteria. The most common innovative substances, metal and metal oxide nanoparticles (NPs), have been widely reported. Until recently, DNA nanostructures were used alone or functionalized with specific DNA sequences by many scholars for antimicrobial purposes which were alternatively selected as therapy for severe bacterial infections. These are a potential candidate for treatments and have a considerable role in killing antibiotic-resistant bacteria. This review involves the dimensions of multidrug resistance and the mechanism of bacteria developing drug resistance. The importance of this article is that we summarized the current study of nano-materials based on nucleic acids in antimicrobial use. Meanwhile, the current progress and the present obstacles for their antibacterial and therapeutic use and special function of stem cells in this field are also discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Paclitaxel is a potent antineoplastic agent, but poor solubility and resistance have limited its use. Gold nanoparticles (AuNPs) are widely studied as drug carriers because they can be engineered to prevent drug insolubility, carry nucleic acid payloads for gene therapy, target specific tumor cell lines, modulate drug release and amplify photothermal therapy. Consequently, the conjugation of paclitaxel with AuNPs to improve antiproliferative and pro‑apoptotic potency may enable improved clinical outcomes. There are currently a number of different AuNPs under development, including simple drug or nucleic acid carriers and targeted AuNPs that are designed to deliver therapeutic payloads to specific cells. The current study reviewed previous research on AuNPs and the development of AuNP‑based paclitaxel delivery.

Nucleic acid aptamers are innovative and promising candidates to block the hallmark event in the prion diseases, that is the conversion of prion protein (PrP) into an abnormal form; however, they need chemical modifications for effective therapeutic activity. This communication reports on the development and biophysical characterization of a small library of chemically modified G-quadruplex-forming aptamers targeting the cellular PrP and the evaluation of their anti-prion activity. The results show the possibility of enhancing anti-prion aptamer properties through straightforward modifications.