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.

Effects of Puerarin-Loaded Tetrahedral Framework Nucleic Acids on Osteonecrosis of the Femoral Head.

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.

Bioswitchable Delivery of microRNA by Framework Nucleic Acids: Application to Bone Regeneration.

MicroRNAs (miRs) play an important role in regulating gene expression. Limited by their instabilities, miR therapeutics require delivery vehicles. Tetrahedral framework nucleic acids (tFNAs) are potentially applicable to drug delivery because they prominently penetrate tissue and are taken up by cells. However, tFNA-based miR delivery strategies have failed to separate the miRs after they enter cells, affecting miR efficiency. In this study, an RNase H-responsive sequence is applied to connect a sticky-end tFNA (stFNA) and miR-2861, which is a model miR, to target the expression of histone deacetylase 5 (HDAC5) in bone marrow mesenchymal stem cells. The resultant bioswitchable nanocomposite (stFNA-miR) enables efficient miR-2861 unloading and deployment after intracellular delivery, thereby inhibiting the expression of HDAC5 and promoting osteogenic differentiation. stFNA-miR also facilitated ideal bone repair via topical injection. In conclusion, a versatile miR delivery strategy is offered for various biomedical applications that necessitate modulation of gene expression.

Tetrahedral Framework Nucleic Acids Deliver Antimicrobial Peptides with Improved Effects and Less Susceptibility to Bacterial Degradation.

Antimicrobial peptides (AMPs) have been an attractive alternative to traditional antibiotics. However, considerable efforts are needed to further enhance their antimicrobial effects and stability against bacterial degradation. Tetrahedral framework nucleic acids (tFNAs), a new class of three-dimensional nanostructures, have been utilized as a delivery vehicle. In this study, tFNAs were combined for the first time with an antimicrobial peptide GL13K, and the effects of the resultant complexes against Escherichia coli (sensitive to GL13K) and Porphyromonas gingivalis (capable of degrading GL13K) were investigated. tFNA-based delivery enhanced the effects of GL13K against E. coli. The tFNA vehicle both increased bacterial uptake and promoted membrane destabilization. Moreover, it enhanced the effects of GL13K against P. gingivalis by protecting the peptide against degradation in the protease-rich extracellular environment. Therefore, tFNA provides a delivery vehicle for AMPs targeting a broad range of disease.

Tetrahedral Framework Nucleic Acids Promote Corneal Epithelial Wound Healing in Vitro and in Vivo.

Poor post-traumatic wound healing can affect the normal function of damaged tissues and organs. For example, poor healing of corneal epithelial injuries may lead to permanent visual impairment. It is of great importance to find a therapeutic way to promote wound closure. Tetrahedral framework nucleic acids (tFNAs) are new promising nanomaterials, which can affect the biological behavior of cells. In the experiment, corneal wound healing is used as an example to explore the effect of tFNAs on wound healing. Results show that the proliferation and migration of human corneal epithelial cells are enhanced by exposure to tFNAs in vitro, possibly relevant to the activation of P38 and ERK1/2 signaling pathway. An animal model of corneal alkali burn is established to further identify the facilitation effect of tFNAs on corneal wound healing in vivo. Clinical evaluations and histological analyses show that tFNAs can improve the corneal transparency and accelerate the re-epithelialization of wounds. Both in vitro and in vivo experiments show that tFNAs can play a positive role in corneal epithelial wound healing.

Targeted and effective glioblastoma therapy via aptamer-modified tetrahedral framework nucleic acid-paclitaxel nanoconjugates that can pass the blood brain barrier.

Targeted DNA nanoparticles have been identified as one of the most promising nanocarriers in anti-glioma drug delivery. We established a multifunctional nanosystem for targeted glioma therapy. Tetrahedral framework nucleic acid (tFNA), entering U87MG cells and bEnd.3 cells, was chosen to deliver two aptamers, GMT8 and Gint4.T, and paclitaxel. GMT8 and Gint4.T, which specifically bind with U87MG cells and with PDGFRß, were linked with tFNA, to form Gint4.T-tFNA-GMT8 (GTG). GTG was efficiently internalized by U87MG and bEnd.3 cells and penetrated an in-vitro blood-brain-barrier model. GTG loaded with paclitaxel (GPC) had potentiated anti-glioma efficacy. It inhibited the proliferation, migration, and invasion of U87MG cells, and enhanced apoptosis induction in these cells. The expression of apoptosis-related proteins was significantly changed after treatment with GPC, confirming apoptosis induction. Our study demonstrated that the combination of GTG and paclitaxel has great potential for glioma treatment and tFNA shows great promise for use in drug delivery.

Effects of sterilization and disinfection methods on digitally designed surgical implant guide accuracy: An in vitro study.

INTRODUCTION: Surgical guides are commonly used to assist with dental implant placement. This study investigated the effects of five sterilization and disinfection methods on the accuracy of implant guides. METHODS: Thirty surgical guides (five in each group) were designed and printed (with digital light processing technology) using different sterilization or disinfection methods categorized into six groups: hydrogen peroxide sterilization (group one); glutaraldehyde sterilization (group two); autoclaving (group three); plasma sterilization (group four); iodophor disinfection (group five); and blank group (group six). Verification was determined using three methods: distance and angle between the cross-shaped marks, deformation after superimposing the guides, and displacement and axial changes in the virtual implant. RESULTS: After disinfection and sterilization, the guides in the autoclaving and iodophor groups showed a more pronounced color change and the guide in the autoclaving group had visible cracks. More significant changes were observed in the H2O2, glutaraldehyde, autoclaving, and iodophor groups regarding deformation after superimposing the guides and the distance and angle between the cross-shaped marks. The average labial deformation values (mm) of the first through fifth groups of guides were 0.283, 0.172, 0.289, 0.153, and 0.188, respectively. All groups were statistically different from the blank group for displacement and axial changes of the virtual implant (p < 0.05). CONCLUSION: The sizes of almost all surgical guides changed after sterilization and disinfection treatments, with between-group differences. Plasma sterilization was more suitable for surgical guide sterilization because of the smaller deformations after treatment.

A Novel Bioswitchable miRNA Mimic Delivery System: Therapeutic Strategies Upgraded from Tetrahedral Framework Nucleic Acid System for Fibrotic Disease Treatment and Pyroptosis Pathway Inhibition.

There has been considerable interest in gene vectors and their role in regulating cellular activities and treating diseases since the advent of nucleic acid drugs. MicroRNA (miR) therapeutic strategies are research hotspots as they regulate gene expression post-transcriptionally and treat a range of diseases. An original tetrahedral framework nucleic acid (tFNA) analog, a bioswitchable miR inhibitor delivery system (BiRDS) carrying miR inhibitors, is previously established; however, it remains unknown whether BiRDS can be equipped with miR mimics. Taking advantage of the transport capacity of tetrahedral framework nucleic acid (tFNA) and upgrading it further, the treatment outcomes of a traditional tFNA and BiRDS at different concentrations on TGF-ß- and bleomycin-induced fibrosis simultaneously in vitro and in vivo are compared. An upgraded traditional tFNA is designed by successfully synthesizing a novel BiRDS, carrying a miR mimic, miR-27a, for treating skin fibrosis and inhibiting the pyroptosis pathway, which exhibits stability and biocompatibility. BiRDS has three times higher efficiency in delivering miRNAs than the conventional tFNA with sticky ends. Moreover, BiRDS is more potent against fibrosis and pyroptosis-related diseases than tFNAs. These findings indicate that the BiRDS can be applied as a drug delivery system for disease treatment.

A Bioswitchable MiRNA Delivery System: Tetrahedral Framework DNA-Based miRNA Delivery System for Applications in Wound Healing.

The human body's primary line of defense, the skin, is especially prone to harm. Although microRNA (miRNA)-based therapies have attracted increasing attention for skin wound healing, their applications remain limited owing to a range of issues. Tetrahedral framework DNA (tFNA), a nanomaterial possessing nucleic acid characteristics, exhibits an excellent biocompatibility, in addition to anti-inflammatory and transdermal delivery capabilities, and can accelerate skin wound healing. Due to its potential to exert synergistic action with therapeutic miRNA, tFNA has been considered an ideal vehicle for miRNA therapy. The design and synthesis of a bioswitchable miRNA delivery system (BiRDS) is reported, which contains three miRNAs as well as a nucleic acid core to maximize the loading capacity while preserving the characteristics of tFNA. A high stability, excellent permeability of cells as well as tissues and good biological compatibility are demonstrated. By selectively inhibiting heparin-binding epidermal growth factor (HB-EGF), the BiRDS can inhibit the NF-κB pathway while simultaneously controlling the PTEN/Akt pathway. As a result, the BiRDS helps wound healing go through the inflammation to the proliferative phase. This study demonstrates the advantages of the BiRDS in miRNA-based therapy and provides new research ideas for the treatment of skin-related diseases.

DNA framework signal amplification platform-based high-throughput systemic immune monitoring.

Systemic immune monitoring is a crucial clinical tool for disease early diagnosis, prognosis and treatment planning by quantitative analysis of immune cells. However, conventional immune monitoring using flow cytometry faces huge challenges in large-scale sample testing, especially in mass health screenings, because of time-consuming, technical-sensitive and high-cost features. However, the lack of high-performance detection platforms hinders the development of high-throughput immune monitoring technology. To address this bottleneck, we constructed a generally applicable DNA framework signal amplification platform (DSAP) based on post-systematic evolution of ligands by exponential enrichment and DNA tetrahedral framework-structured probe design to achieve high-sensitive detection for diverse immune cells, including CD4+, CD8+ T-lymphocytes, and monocytes (down to 1/100 µl). Based on this advanced detection platform, we present a novel high-throughput immune-cell phenotyping system, DSAP, achieving 30-min one-step immune-cell phenotyping without cell washing and subset analysis and showing comparable accuracy with flow cytometry while significantly reducing detection time and cost. As a proof-of-concept, DSAP demonstrates excellent diagnostic accuracy in immunodeficiency staging for 107 HIV patients (AUC > 0.97) within 30 min, which can be applied in HIV infection monitoring and screening. Therefore, we initially introduced promising DSAP to achieve high-throughput immune monitoring and open robust routes for point-of-care device development.

Recent Progress on Hydrogel-Based Piezoelectric Devices for Biomedical Applications.

Flexible electronics have great potential in the application of wearable and implantable devices. Through suitable chemical alteration, hydrogels, which are three-dimensional polymeric networks, demonstrate amazing stretchability and flexibility. Hydrogel-based electronics have been widely used in wearable sensing devices because of their biomimetic structure, biocompatibility, and stimuli-responsive electrical properties. Recently, hydrogel-based piezoelectric devices have attracted intensive attention because of the combination of their unique piezoelectric performance and conductive hydrogel configuration. This mini review is to give a summary of this exciting topic with a new insight into the design and strategy of hydrogel-based piezoelectric devices. We first briefly review the representative synthesis methods and strategies of hydrogels. Subsequently, this review provides several promising biomedical applications, such as bio-signal sensing, energy harvesting, wound healing, and ultrasonic stimulation. In the end, we also provide a personal perspective on the future strategies and address the remaining challenges on hydrogel-based piezoelectric electronics.

Minimally invasive techniques for lateral maxillary sinus floor elevation: small lateral window and one-stage surgery-a 2-5-year retrospective study.

This study aimed to introduce a minimally invasive technique for maxillary sinus floor elevation using the lateral approach (lSFE) and to determine the factors that influence the stability of the grafted area in the sinus cavity. Thirty patients (30 implants) treated with lSFE using minimally invasive techniques from 2015 to 2019 were included in the study. Five aspects of the implant (central, mesial, distal, buccal, and palatal bone heights [BHs]) were measured using cone-beam computed tomography (CBCT) before implant surgery, immediately after surgery (T0), 6 months after surgery (T1), and at the last follow-up visit (T2). Patients' characteristics were collected. A small bone window (height, (4.40 ± 0.74) mm; length, (6.26 ± 1.03) mm) was prepared. No implant failed during the follow-up period (3.67 ± 1.75) years. Three of the 30 implants exhibited perforations. Changes in BH of the five aspects of implants showed strong correlations with each other and BH decreased dramatically before second-stage surgery. Residual bone height (RBH) did not significantly influence BH changes, whereas smoking status and type of bone graft materials were the potentially influential factors. During the approximate three-year observation period, lSFE with a minimally invasive technique demonstrated high implant survival rate and limited bone reduction in grafted area. In conclusion, lSFE using minimally invasive techniques was a viable treatment option. Patients who were nonsmokers and whose sinus cavity was filled with deproteinized bovine bone mineral (DBBM) had significantly limited bone resorption in grafted area.

A minimally invasive method for titanium mesh fixation with resorbable sutures in guided bone regeneration: A retrospective study.

OBJECTIVES: Titanium mesh has become a mainstream choice for guided bone regeneration (GBR) owing to its excellent space maintenance. However, the traditional fixation method using titanium screws impacts surgery efficiency and increases patient trauma. We report a novel method of fixing a titanium mesh using resorbable sutures. We assessed the feasibility of resorbable sutures for fixing a titanium mesh and whether it can serve as a stable, universal, and minimally invasive fixation method for a broader application of titanium meshes. METHODS: Patients undergoing GBR with a digital titanium mesh fixed using titanium screws (TS group) and resorbable sutures (RS group) were observed at different time points. The stability of the fixation methods was evaluated on parameters such as titanium mesh spatial displacement, bone augmentation, and bone resorption. RESULTS: A total of 36 patients were included in this study. The exposure rate of the titanium mesh in the TS group was 16.67%, while no exposure was noted in the RS group. There was no significant difference in the parameters of titanium mesh spatial displacement, bone augmentation, and bone resorption between the two groups (p > 0.05). CONCLUSION: The use of resorbable sutures for fixing a titanium mesh can achieve similar results to traditional fixation using titanium screws. Although this new fixation method can improve the efficiency of the surgery and reduce the risk of complications, the long-term clinical effects require further follow-up investigation.

Tetrahedral framework nucleic acid nanomaterials reduce the inflammatory damage in sepsis by inhibiting pyroptosis.

Sepsis is a highly lethal condition and is caused by the dysregulation of the body's immune response to infection. Indeed, sepsis remains the leading cause of death in severely ill patients, and currently, no effective treatment is available. Pyroptosis, which is mainly activated by cytoplasmic danger signals and eventually promote the release of the pro-inflammatory factors, is a newly discovered programmed cell death procedure that clears infected cells while simultaneously triggering an inflammatory response. Increasing evidence indicates that pyroptosis participates in the development of sepsis. As a novel DNA nanomaterial, tetrahedral framework nucleic acids (tFNAs) characterized by its unique spatial structure, possess an excellent biosafety profile and can quickly enter the cell to impart anti-inflammatory and anti-oxidation effects. In this study, the roles of tFNAs in the in vitro model of macrophage cell pyroptosis and in the in vivo model of septic mice were examined, and it was found that tFNAs could mitigate organ inflammatory damage in septic mice, wherein they reduced inflammatory factor levels by inhibiting pyroptosis. These results provide possible new strategies for the future treatment of sepsis.

Functional micro-RNA drugs acting as a fate manipulator in the regulation of osteoblastic death.

Bone loss is prevalent in clinical pathological phenomena such as osteoporosis, which is characterized by decreased osteoblast function and number, increased osteoclast activity, and imbalanced bone homeostasis. However, current treatment strategies for bone diseases are limited. Regulated cell death (RCD) is a programmed cell death pattern activated by the expression of specific genes in response to environmental changes. Various studies have shown that RCD is closely associated with bone diseases, and manipulating the death fate of osteoblasts could contribute to effective bone treatment. Recently, microRNA-targeting therapy drugs have emerged as a potential solution because of their precise targeting, powerful curative effect, and limited side effects. Nevertheless, their clinical application is limited by their inherent instability, easy enzymatic degradation, and poor membrane penetrability. To address this challenge, a self-assembling tetrahedral DNA nanostructure (TDN)-based microRNA (Tmi) delivery system has been proposed. TDN features excellent biocompatibility, cell membrane penetrability, serum stability, and modification versatility, making it an ideal nucleic acid carrier for miRNA protection and intracellular transport. Once inside cells, Tmi can dissociate and release miRNAs to manipulate key molecules in the RCD signaling pathway, thereby regulating bone homeostasis and curing diseases caused by abnormal RCD activation. In this paper, we discuss the impact of the miRNA network on the initiation and termination of four critical RCD programs in bone tissues: apoptosis, autophagy, pyroptosis, and ferroptosis. Furthermore, we present the Tmi delivery system as a miRNA drug vector. This provides insight into the clinical translation of miRNA nucleic acid drugs and the application of miRNA drugs in bone diseases.

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.

Liver-Targeted Delivery of Small Interfering RNA of C-C Chemokine Receptor 2 with Tetrahedral Framework Nucleic Acid Attenuates Liver Cirrhosis.

Liver cirrhosis is the end stage of chronic liver diseases without approved clinical drugs. In this study, a new strategy that uses a C-C chemokine receptor 2 (CCR2) small interfering RNA silencing (siCcr2)-based therapy by loading multivalent siCcr2 with tetrahedron framework DNA nanostructure (tFNA) vehicle (tFNA-siCcr2) was established to attenuate liver fibrosis. tFNA-siCcr2 was successfully synthesized without changing the physiochemical properties of tFNA. Compared to the naked siCcr2 molecule, the tFNA-siCcr2 complex altered the accumulation from the kidney to the liver after the intraperitoneal injection. The tFNA-siCcr2 complex also prolonged hepatic retention and mainly colocalized within macrophages and endothelial cells. tFNA-siCcr2 efficiently silenced CCR2 and significantly ameliorated liver fibrosis in prevention and treatment interventions. Single-cell RNA sequencing followed by experimental validation suggested that tFNA-siCcr2 can restore the immune cell landscape and construct an antifibrotic niche by inhibiting profibrotic macrophage and neutrophil accumulation in the murine fibrotic liver. Molecularly, the tFNA-siCcr2 complex reduced inflammatory mediator production by inactivating the NF-κB signaling pathway. In conclusion, the tFNA-based liver-targeted tFNA-siCcr2 delivery complex efficiently ameliorated liver fibrosis by restoring the immune cell landscape and constructing an antifibrotic niche, which makes the tFNA-siCcr2 complex a potential therapeutic candidate for the clinical treatment of liver cirrhosis.

Tetrahedral Framework Nucleic Acids Connected with MicroRNA-126 Mimics for Applications in Vascular Inflammation, Remodeling, and Homeostasis.

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.

Tetrahedral framework nucleic acids-based delivery promotes intracellular transfer of healing peptides and accelerates diabetic would healing.

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.

Tetrahedral-Framework Nucleic Acids Carry Small Interfering RNA to Downregulate Toll-Like Receptor 2 Gene Expression for the Treatment of Sepsis.

Sepsis is caused by the invasion of pathogenic microorganisms, which can lead to excessive expression of toll-like receptors (TLRs) in cells and uncontrollable amplification of the inflammatory response. TLR2, as an essential part of the TLR family, has a significant feature in the identification of innate immune responses. Therefore, blocking the expression and activation of TLR2 can inhibit the synthesis and release of inflammatory factors and avoid the occurrence of excessive inflammatory reactions. Small interfering RNA (siRNA) can selectively target the silencing or downregulation of pathogenic genes and has the advantages of high specificity, a strong effect, and fewer adverse reactions. However, the application of siRNA is limited by its high molecular weight, poor biostability, and difficulty in passive uptake into cells. Tetrahedral-framework nucleic acid (tFNA) is a new kind of three-dimensional nucleic acid nanomaterial, which has the advantages of good biocompatibility, stable structure, and editability. In this study, we used tFNA as carriers to deliver siRNA-targeting downregulation of TLR2 expression for anti-inflammatory therapy. We show that siRNA can specifically reduce lipopolysaccharide (LPS)-induced TLR2 elevation and reduce release of inflammatory factors in LPS-induced experimental sepsis, which provides a new idea for the prevention and treatment of sepsis.