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Tetrahedral Framework Nucleic Acid-Based Delivery of Resveratrol Alleviates Insulin Resistance:From Innate to Adaptive Immunity

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Nano-Micro Letters 2021年第6期13卷 1-16页

作者： Yanjing Li Shaojingya Gao sirong shi Dexuan Xiao Shuanglin Peng Yang Gao Ying Zhu Yunfeng Lin State Key Laboratory of Oral Diseases West China Hospital of StomatologySichuan UniversityChengdu 610041P.R.China Department of Oral and Maxillofacial Surgery Hospital of StomatologySouthwest Medical UniversityLuzhou 646000P.R.China Zhangjiang Laboratory Shanghai Advanced Research InstituteChinese Academy of SciencesShanghai 201210P.R.China CAS Key Laboratory of Interfacial Physics and Technology Division of Physical BiologyShanghai Institute of Applied PhysicsShanghai Synchrotron Radiation FacilityChinese Academy of SciencesShanghai 201800P.R.China College of Biomedical Engineering Sichuan UniversityChengdu 610041P.R.China

Obesity-induced insulin resistance is the hallmark of metabolic syndrome,and chronic,low-grade tissue inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune *** therapeutic approaches lack efficacy and immunomodulatory ***,a new therapeutic approach is needed to prevent chronic inflammation and alleviate insulin ***,we synthesized a tetrahedral framework nucleic acid(tFNA)nanoparticle that carried resveratrol(RSV)to inhibit tissue inflammation and improve insulin sensitivity in obese *** prepared nanoparticles,namely tFNAs-RSV,possessed the characteristics of simple synthesis,stable properties,good water solubility,and superior *** tFNA-based delivery ameliorated the lability of RSV and enhanced its therapeutic *** high-fat diet(HFD)-fed mice,the administration of tFNAs-RSV ameliorated insulin resistance by alleviating inflammation ***-RSV could reverse M1 phenotype macrophages in tissues to M2 phenotype *** for adaptive immunity,the prepared nanoparticles could repress the activation of Th1 and Th17 and promote Th2 and Treg,leading to the alleviation of insulin ***,this study is the first to demonstrate that tFNAs,a nucleic acid material,possess immunomodulatory ***,our findings demonstrate that tFNAs-RSV alleviate insulin resistance and ameliorate inflammation in HFD mice,suggesting that nucleic acid materials or nucleic acid-based delivery systems may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.

关键词： Tetrahedral framework nucleic acid Resveratrol Insulin resistance Inflammation Innate immunity Adaptive immunity

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The fabrication of biomimetic biphasic CAN-PAC hydrogel with a seamless interfacial layer applied in osteochondral defect repair

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Bone Research 2017年第2期5卷 137-151页

作者： Jinfeng Liao Taoran Tian sirong shi Xueping Xie Quanquan Ma Guo Li Yunfeng Lin State Key Laboratory of Oral Diseases National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu China

Cartilage tissue engineering based on biomimetic scaffolds has become a rapidly developing strategy for repairing cartilage defects. In this study, a biphasic CAN-PAC hydrogel for osteochondral defect(OCD)regeneration was fabricated based on the density difference between the two layers via a thermally reactive,rapid cross-linking method. The upper hydrogel was cross-linked by CSMA and NIPAm, and the lower hydrogel was composed of PECDA, AAm and PEGDA. The interface between the two layers was first grafted by the physical cross-linking of calcium gluconate and alginate, followed by the chemical cross-linking of the carbon-carbon double bonds in the other components. The pore sizes of the upper and lower hydrogels were ~ 187.4 and ~ 112.6 μm, respectively. The moduli of the upper and lower hydrogels were ~ 0.065 and~ 0.261 MPa. This prepared bilayer hydrogel exhibited the characteristics of mimetic composition, mimetic structure and mimetic stiffness, which provided a microenvironment for sustaining cell attachment and viability. Meanwhile, the biodegradability and biocompatibility of the CAN-PAC hydrogel were examined in vivo. Furthermore, an osteochondral defect model was developed in rabbits, and the bilayer hydrogels were implanted into the defect. The regenerated tissues in the bilayer hydrogel group exhibited new translucent cartilage and repaired subchondral bone, indicating that the hydrogel can enhance the repair of osteochondral defects.

关键词： hydrogel biomimetic fabrication

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A tetrahedral framework nucleic acid based multifunctional nanocapsule for tumor prophylactic mRNA vaccination

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Chinese Chemical Letters 2023年第7期34卷 169-175页

作者： Yuhao Liu Songhang Li shiyu Lin sirong shi Taoran Tian Bowen Zhang Tao Zhang Yunfeng Lin State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan University Chengdu 610041China Key Laboratory of Oral Biomedical Research of Zhejiang Province Zhejiang UniversityHangzhou 31000China Guanghua School of Stomatology Guangdong Provincial Key Laboratory of StomatologySun Yat-sen UniversityGuangzhou 510055China

Synthetic antigen-encoding mRNA plays an increasingly significant role in tumor vaccine technology owing to its antigen-specific immune-activation. However, its immune efficacy is challenged by inferior delivery efficiency and demand for suitable adjuvants. Here, we develop a novel mRNA nanovaccine based on a multifunctional nanocapsule, which is a dual-adjuvant formulation composed of cytosine-phosphateguanine motifs loaded tetrahedral framework nucleic acid(CpG-tFNA) and an immunopeptide murine β-defensin 2(mDF2β). This m RNA nanovaccine successfully achieves intracellular delivery, antigen expression and presentation of dendritic cells, and proliferation of antigen-specific T cells. In a tumor prophylactic vaccination model, it exerts an excellent inhibitory effect on lymphoma occurrence through cellular immunity. This mRNA nanovaccine has promising prophylactic applications in tumors and many other diseases.

关键词： Tetrahedral framework nucleic acid(tFNA) RNA nanovaccine Cytosine-phosphate-guanine(CpG)motifs Murineβ-defensin 2(mDF2β) Tumor immunotherapy

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Tetrahedral framework nucleic acids regulate osteogenic differentiation potential of osteoporotic adipose-derived stem cells

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Chinese Chemical Letters 2022年第5期33卷 2517-2521页

作者： Tianyu Chen Dexuan Xiao Yanjing Li sirong shi Xiao Yang Shuanglin Peng Bin Guo Xiaoxiao Cai State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengdu 610041China Department of Stomatology First Medical Center of Chinese PLA General HospitalBeijing 100853China

Osteoporosis(OP)is a noncommunicable bone disease caused by a shift in the balance between os-teoblasts and osteoclasts,and can severely affect the health of elderly *** stem-cell transplantation can improve reduced bone density and weakened fracture healing abilities in patients with ***,OP can adversely affect the osteogenesis and proliferation abilities of autologous adipose-derived stem cells(ASCs).Therefore,an effective drug is required to facilitate autologous ASCs to recover their osteogenic and proliferative *** framework nucleic acid(tFNA)is a new type of nanomaterial that has ability to regulate the biological behavior of cells effectively and en-hance the bioactivity of stem *** this study,we examine the effects of tFNAs on the osteogenic differentiation and proliferation abilities of ASCs in rats with *** results indicate that the 250 nmol/L tFNAs can considerably increase the expression of osteogenesis-related markers,effectively promote the proliferation and osteogenic differentiation of osteoporotic ASCs(OP-ASCs),and help them to regain their osteogenic and proliferative *** short,tFNAs can enable OP-ACSs to recover their osteogenic po-tential and promote their proliferation and,therefore,can play a key regulatory role in autologous ASC transplantation.

关键词： Osteoporosis Tetrahedral framework nucleic acid Adipose-derived stem cell Autologous stem-cell transplantation Osteogenic differentiation

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Transdermal treatment for malignant melanoma by aptamer-modified tetrahedral framework nucleic acid delivery of vemurafenib

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Chinese Chemical Letters 2024年第4期35卷 260-267页

作者： Dexuan Xiao Tianyu Chen Tianxu Zhang sirong shi Mei Zhang Xin Qin Yunkun Liu Longjiang Li Yunfeng Lin State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengdu 610041China Sichuan Provincial Engineering Research Center of Oral Biomaterials Chengdu 610041China Department of Head and Neck Oncology National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengdu 610041China

Melanoma is one of the most malignant skin tumors, whose high invasion is generally associated with BRAF gene mutation. Although new chemotherapeutic drugs, such as vemurafenib, have been developed to inhibit the growth of melanoma, these drugs are usually administered intravenously or orally, resulting in toxic side effects on major tissues and organs. Tetrahedral framework nucleic acids(tFNAs) are a novel type of DNA nanostructures with excellent biocompatibility and versatility which have been proven to penetrate through skin barrier with ease. In this study, we prepared t FNAs with vemurafenib and connected DNA aptamer AS1411 at the apex of t FNAs(AS1411-tFNAs/vemurafenib). On one hand, AS1411-tFNAs/vemurafenib could kill melanoma cells by blocking the mutated BRAF gene in vitro. Compared with free vemurafenib, AS1411-tFNAs/vemurafenib had no obvious toxicity to normal cells. On the other hand,AS1411-tFNAs could transfer vemurafenib to cross through the skin barrier and permeate into tumor tissues. In vivo, transdermal delivery of AS1411-t FNAs/vemurafenib could inhibit the growth of human A375melanoma, whose inhibiting effect was stronger than intravenous administration of vemurafenib. These results demonstrated the application prospects of tFNAs combined with chemotherapeutic drugs in skin tumors.

关键词： Melanoma Vemurafenib DNA nanostructure Transdermal treatment Side effect

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Effects of tetrahedral framework nucleic acid/wogonin complexes on osteoarthritis

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Bone Research 2020年第1期8卷 84-96页

作者： sirong shi Yang Chen Taoran Tian Songhang Li shiyu Lin Yuxin Zhang Xiaoru Shao Tao Zhang Yunfeng Lin Xiaoxiao Cai State Key Laboratory of Oral Disease National Clinical Research Center for Oral DiseasesWest China Hosptial of StomatologySichuan UniversityChengdu 610041China Department of Liver Surgery&Liver Transplantation Center West China Hospital of Sichuan UniversityChengdu 610041 Sichuan ProvinceChina

Osteoarthritis, a disorder characterized by articular cartilage deterioration, varying degrees of inflammation, and chondrocyte apoptosis, is the most common chronic joint disease. To slow or reverse its progression, inflammation should be inhibited, and chondrocyte proliferation should be promoted. Tetrahedral framework nucleic acids can be internalized by chondrocytes(even inflammatory chondrocytes) and can enhance their proliferation and migration. Wogonin, a naturally occurring flavonoid,suppresses oxidative stress and inhibits inflammation. In this study, tetrahedral framework nucleic acids were successfully selfassembled and used to load wogonin. We confirmed the effective formation of tetrahedral framework nucleic acid/wogonin complexes by dynamic light scattering, zeta potential analysis, transmission electron microscopy, and fluorescence spectrophotometry. Tetrahedral framework nucleic acids, wogonin, and especially tetrahedral framework nucleic acid/wogonin complexes effectively alleviated inflammation in vitro and in vivo and prevented cartilage destruction. In addition, these materials remarkably downregulated the expression of inflammatory mediators and matrix metalloproteinases, upregulated chondrogenic markers, and promoted tissue inhibitor of metalloproteinase 1 and B-cell lymphoma 2 expression. In vivo, after treatment with tetrahedral framework nucleic acid/wogonin complexes, the bone mineral density in regenerated tissues was much higher than that found in the untreated groups. Histologically, the complexes enhanced new tissue regeneration, significantly suppressed chondrocyte apoptosis, and promoted chondrogenic marker expression. They also inhibited cell apoptosis, increased chondrogenic marker expression, and suppressed the expression of inflammatory mediators in osteoarthritis. Therefore, we believe that tetrahedral framework nucleic acid/wogonin complexes can be used as an injectable form of therapy for osteoarthritis.

关键词： complexes tetrahedral promoted

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Tetrahedral framework nucleic acids enhance the chondrogenic potential of human umbilical cord mesenchymal stem cells via the PI3K/AKT axis

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Regenerative Biomaterials 2023年第1期10卷 1552-1565页

作者： Liwei Fu Pinxue Li Jiang Wu Yazhe Zheng Chao Ning Zhiyao Liao Xun Yuan Zhengang Ding Zhichao Zhang Xiang Sui sirong shi Shuyun Liu Quanyi Guo School of Medicine Nankai UniversityTianjin 300071People’s Republic of China Institute of Orthopedics Chinese PLA General HospitalBeijing Key Laboratory of Regenerative Medicine in OrthopedicsKey Laboratory of Musculoskeletal Trauma&War Injuries PLABeijing 100853People’s Republic of China Guizhou Medical University GuiyangGuizhou 550004People’s Republic of China State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengdu 610041People’s Republic of China

The field of regenerative medicine faces a notable challenge in terms of the regeneration of articular *** proper treatment,it can lead to *** on the research findings,human umbilical cord mesenchymal stem cells(hUMSCs)are considered an excellent choice for regenerating ***,there is still a lack of suitable biomaterials to control their ability to self-renew and *** address this issue,in this study using tetrahedral framework nucleic acids(tFNAs)as a new method in an in vitro culture setting to manage the behaviour of hUMSCs was ***,the influence of tFNAs on hUMSC proliferation,migration and chondrogenic differentiation was explored by combining bioinformatics *** addition,a variety of molecular biology techniques have been used to investigate deep molecular *** results demonstrated that tFNAs can affect the transcriptome and multiple signalling pathways of hUMSCs,among which the PI3K/Akt pathway is significantly ***,tFNAs can regulate the expression levels of multiple proteins(GSK3β,RhoA and mTOR)downstream of the PI3K-Akt axis to further enhance cell proliferation,migration and hUMSC chondrogenic *** provide new insight into enhancing the chondrogenic potential of hUMSCs,which exhibits promising potential for future utilization within the domains of AC regeneration and clinical treatment.

关键词： tFNAs articular cartilage hUMSCs chondrogenic differentiation

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Advances in regenerative medicine applications of tetrahedral framework nucleic acid-based nanomaterials: an expert consensus recommendation

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International Journal of Oral Science 2022年第4期14卷 439-460页

作者： Yunfeng Lin Qian Li Lihua Wang Quanyi Guo Shuyun Liu shihui Zhu Yu Sun Yujiang Fan Yong Sun Haihang Li Xudong Tian Delun Luo sirong shi State Key Laboratory of Oral Diseases&National Clinical Research Center for Oral Diseases&Department of Oral and Maxillofacial Surgery West China Hospital of StomatologySichuan UniversityChengduChina School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative MoleculesInstitute of Translational MedicineShanghai Jiao Tong UniversityShanghaiChina The Interdisciplinary Research Center Shanghai Advanced Research InstituteChinese Academy of SciencesZhangjiang LaboratoryShanghaiChina Institute of Orthopedics Chinese PLA General HospitalBeijing Key Laboratory of Regenerative Medicine in OrthopedicsKey Laboratory of Musculoskeletal Trauma&War Injuries PLABejingChina Department of Burn Surgery The First Affliated Hospital of Naval Medical UniversityShanghaiChina National Engineering Research Center for Biomaterials Sichuan UniversityChengduChina College of Biomedical Engineering Sichuan UniversityChengduChina Jiangsu Trautec Medical Technology Company Limited ChangzhouChina Chengdu Jingrunze Gene Technology Company Limited ChengduChina

With the emergence of DNA nanotechnology in the 1980s, self-assembled DNA nanostructures have attracted considerable attention worldwide due to their inherent biocompatibility, unsurpassed programmability, and versatile functions. Especially promising nanostructures are tetrahedral framework nucleic acids(t FNAs), first proposed by Turberfield with the use of a one-step annealing approach. Benefiting from their various merits, such as simple synthesis, high reproducibility, structural stability, cellular internalization, tissue permeability, and editable functionality, t FNAs have been widely applied in the biomedical field as threedimensional DNA nanomaterials. Surprisingly, t FNAs exhibit positive effects on cellular biological behaviors and tissue regeneration,which may be used to treat inflammatory and degenerative diseases. According to their intended application and carrying capacity,t FNAs could carry functional nucleic acids or therapeutic molecules through extended sequences, sticky-end hybridization,intercalation, and encapsulation based on the Watson and Crick principle. Additionally, dynamic t FNAs also have potential applications in controlled and targeted therapies. This review summarized the latest progress in pure/modified/dynamic t FNAs and demonstrated their regenerative medicine applications. These applications include promoting the regeneration of the bone,cartilage, nerve, skin, vasculature, or muscle and treating diseases such as bone defects, neurological disorders, joint-related inflammatory diseases, periodontitis, and immune diseases.

关键词： tetrahedral summarized versatile

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A novel mesenchymal stem cell-targeting dual-miRNA delivery system based on aptamer-functionalized tetrahedral framework nucleic acids:Application to endogenous regeneration of articular cartilage

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Bioactive Materials 2024年第10期40卷 634-648页

作者： Liwei Fu Jiang Wu Pinxue Li Yazhe Zheng Zhichao Zhang Xun Yuan Zhengang Ding Chao Ning Xiang Sui Shuyun Liu sirong shi Quanyi Guo Yunfeng Lin School of Medicine Nankai UniversityTianjin300071People’s Republic of China Institute of Orthopedics The First Medical CenterChinese PLA General HospitalBeijing Key Lab of Regenerative Medicine in OrthopedicsKey Laboratory of Musculoskeletal Trauma&War Injuries PLANo.28 Fuxing RoadHaidian DistrictBeijingPeople’s Republic of China Department of Orthopedics The Fourth Medical CenterChinese PLA General HospitalBeijingPeople’s Republic of China National Clinical Research Center for Orthopedics Sports Medicine&RehabilitationBeijingPeople’s Republic of China State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengdu610041People’s Republic of China Guizhou Medical University Guiyang550004Guizhou ProvincePeople’s Republic of China

Articular cartilage injury(ACI)remains one of the key challenges in regenerative medicine,as current treatment strategies do not result in ideal regeneration of hyaline-like *** endogenous repair via micro-RNAs(miRNAs)shows promise as a regenerative ***-140 and miRNA-455 are two key and promising candidates for regulating the chondrogenic differentiation of mesenchymal stem cells(MSCs).In this study,we innovatively synthesized a multifunctional tetrahedral framework in which a nucleic acid(tFNA)-based targeting miRNA codelivery system,named A-T-M,was *** tFNAs as vehicles,miR-140 and miR-455 were connected to and modified on tFNAs,while Apt19S(a DNA aptamer targeting MSCs)was directly integrated into the *** relevant results showed that A-T-M efficiently delivered miR-140 and miR-455 into MSCs and subsequently regulated MSC chondrogenic differentiation through corresponding ***,a synergistic effect between miR-140 and miR-455 was ***,A-T-M successfully enhanced the endogenous repair capacity of articular cartilage in vivo and effectively inhibited hypertrophic chondrocyte formation.A-T-M provides a new perspective and strategy for the regeneration of articular cartilage,showing strong clinical application value in the future treatment of ACI.

关键词： Tetrahedral framework nucleic acids miRNAs co-delivery Targeting system Articular cartilage endogenous regeneration Mesenchymal stem cells

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Correction to:Tetrahedral Framework Nucleic Acid‑Based Delivery of Resveratrol Alleviates Insulin Resistance:From Innate to Adaptive Immunity

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Nano-Micro Letters 2021年第11期13卷 423-426页

作者： Yanjing Li Shaojingya Gao sirong shi Dexuan Xiao Shuanglin Peng Yang Gao Ying Zhu Yunfeng Lin State Key Laboratory of Oral Diseases West China Hospital of StomatologySichuan UniversityChengdu 610041People’s Republic of China Department of Oral and Maxillofacial Surgery Hospital of StomatologySouthwest Medical UniversityLuzhou 646000People’s Republic of China Zhangjiang Laboratory Shanghai Advanced Research InstituteChinese Academy of SciencesShanghai 201210People’s Republic of China CAS Key Laboratory of Interfacial Physics and Technology Division of Physical BiologyShanghai Institute of Applied PhysicsShanghai Synchrotron Radiation FacilityChinese Academy of SciencesShanghai 201800People’s Republic of China College of Biomedical Engineering Sichuan UniversityChengdu 610041People’s Republic of China

Correction to:Nano‑Micro Lett.(2021)13:86 https://***/10.1007/s40820-021-00614-6 The Nano-Micro Letters(2021)13:86,article by Li et al.,entitled“Tetrahedral Framework Nucleic Acid‐Based Delivery of Resveratrol Alleviates Insulin Resistance:From Innate to Adaptive Immunity”(Nano-Micro ***://***/10.1007/s40820-021-00614-6),was published online 06 March,2020,with errors.

关键词： nat Resveratrol Delivery

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