Pub Date : 2024-10-19DOI: 10.1016/j.biomaterials.2024.122901
Jia-Wei Wang , Ping Ji , Jin-Yue Zeng , Jun-Long Liang , Qian Cheng , Miao-Deng Liu , Wei-Hai Chen , Xian-Zheng Zhang
Hypoxia and lactate-overexpressed tumor microenvironment always lead to poor therapeutic effect of radiotherapy. Here, platinum nanoparticles-embellished hafnium metal-organic framework (Hf-MOF-Pt NPs) were elaborately integrated with Shewanella oneidensis MR-1 (SO) to construct an engineered biohybrid platform (SO@Hf-MOF-Pt) for enhancing radiotherapy. Benefiting from the tumor-targeting and metabolic respiration characteristics of SO, SO@Hf-MOF-Pt could enrich in tumor sites and continuously metabolize the overexpressed lactate, which specifically downregulated the expression of hypoxia-inducible factor (HIF-1α), thereby relieving the radiosuppressive tumor microenvironment to some extent. Moreover, SO@Hf-MOF-Pt would react with tumor-overexpressed hydrogen peroxide (H2O2) to generate oxygen (O2) and further inhibit the expression of HIF-1α, resulting in the downregulation of lactate dehydrogenase (LDHA) and subsequently reducing the lactate production. Under these multiple cascaded effects, the radiosuppressive tumor microenvironment was significantly reshaped, thus potentiating the radiosentization of SO@Hf-MOF-Pt and remarkably amplifying the therapeutic outcomes of radiotherapy. The designed biohybrid SO@Hf-MOF-Pt represented promising prospects in sensitizing radiotherapy via bacterium-based metabolic regulation.
{"title":"Engineered bacterium-metal-organic framework biohybrids for boosting radiotherapy with multiple effects","authors":"Jia-Wei Wang , Ping Ji , Jin-Yue Zeng , Jun-Long Liang , Qian Cheng , Miao-Deng Liu , Wei-Hai Chen , Xian-Zheng Zhang","doi":"10.1016/j.biomaterials.2024.122901","DOIUrl":"10.1016/j.biomaterials.2024.122901","url":null,"abstract":"<div><div>Hypoxia and lactate-overexpressed tumor microenvironment always lead to poor therapeutic effect of radiotherapy. Here, platinum nanoparticles-embellished hafnium metal-organic framework (Hf-MOF-Pt NPs) were elaborately integrated with <em>Shewanella oneidensis</em> MR-1 (SO) to construct an engineered biohybrid platform (SO@Hf-MOF-Pt) for enhancing radiotherapy. Benefiting from the tumor-targeting and metabolic respiration characteristics of SO, SO@Hf-MOF-Pt could enrich in tumor sites and continuously metabolize the overexpressed lactate, which specifically downregulated the expression of hypoxia-inducible factor (HIF-1α), thereby relieving the radiosuppressive tumor microenvironment to some extent. Moreover, SO@Hf-MOF-Pt would react with tumor-overexpressed hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) to generate oxygen (O<sub>2</sub>) and further inhibit the expression of HIF-1α, resulting in the downregulation of lactate dehydrogenase (LDHA) and subsequently reducing the lactate production. Under these multiple cascaded effects, the radiosuppressive tumor microenvironment was significantly reshaped, thus potentiating the radiosentization of SO@Hf-MOF-Pt and remarkably amplifying the therapeutic outcomes of radiotherapy. The designed biohybrid SO@Hf-MOF-Pt represented promising prospects in sensitizing radiotherapy via bacterium-based metabolic regulation.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122901"},"PeriodicalIF":12.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1016/j.biomaterials.2024.122899
Jingyun Wang , Qin Zhang , Hetong Wang , Chunlin Liu , Le Jiang , Wanting Liu , Yixian Wu , Yifan Wang , Vivian , Hao Yan , Jun Lin , Xiaodan Sun
Chronic osteomyelitis (OM) represents a severe and persistent infectious bone disease. Effective treatment requires controlled anti-inflammatory releases and bone regeneration across disease phases. A Sr@Ag-based scaffold was successfully printed, featuring micron-scale coaxial fibers containing Ag-doped hydroxyapatite (HA) in the outer layer of PLLA and Sr-doped HA in the inner layer of PLLA, facilitating the spatiotemporal and sequential release of Ag and Sr ions during OM treatment. Most antibacterial agent (Ag) was released during the first 20 days, followed by a slow-release plateau over the next 40 days in phosphate-buffered saline solution (PBS). Meanwhile, the pro-angiogenic agent (Sr) was released in minimal amounts during the initial 20 days, followed by a rapid and considerable release in the following 40 days. The coaxial design effectively inhibited the growth of Staphylococcus aureus and Escherichia coli while preserving the viability of bone cells. The ion-based scaffold exhibited broad-spectrum antibacterial effects and enhanced bone-regenerating gene expression in a complex air-bacteria environment. The Sr@Ag-based coaxial scaffold demonstrated effective antibacterial activity during the early stage and exhibited excellent non-toxic bone regeneration results during the middle and late stages in vivo. This work offered a promising treatment strategy through sequential anti-inflammatory and pro-osteogenic effects for infectious bone-defect diseases.
{"title":"A Sr@Ag-based spatiotemporal and step-release scaffold against chronic osteomyelitis, fabricated by coaxial 3D-printing","authors":"Jingyun Wang , Qin Zhang , Hetong Wang , Chunlin Liu , Le Jiang , Wanting Liu , Yixian Wu , Yifan Wang , Vivian , Hao Yan , Jun Lin , Xiaodan Sun","doi":"10.1016/j.biomaterials.2024.122899","DOIUrl":"10.1016/j.biomaterials.2024.122899","url":null,"abstract":"<div><div>Chronic osteomyelitis (OM) represents a severe and persistent infectious bone disease. Effective treatment requires controlled anti-inflammatory releases and bone regeneration across disease phases. A Sr@Ag-based scaffold was successfully printed, featuring micron-scale coaxial fibers containing Ag-doped hydroxyapatite (HA) in the outer layer of PLLA and Sr-doped HA in the inner layer of PLLA, facilitating the spatiotemporal and sequential release of Ag and Sr ions during OM treatment. Most antibacterial agent (Ag) was released during the first 20 days, followed by a slow-release plateau over the next 40 days in phosphate-buffered saline solution (PBS). Meanwhile, the pro-angiogenic agent (Sr) was released in minimal amounts during the initial 20 days, followed by a rapid and considerable release in the following 40 days. The coaxial design effectively inhibited the growth of Staphylococcus aureus and Escherichia coli while preserving the viability of bone cells. The ion-based scaffold exhibited broad-spectrum antibacterial effects and enhanced bone-regenerating gene expression in a complex air-bacteria environment. The Sr@Ag-based coaxial scaffold demonstrated effective antibacterial activity during the early stage and exhibited excellent non-toxic bone regeneration results during the middle and late stages <em>in vivo</em>. This work offered a promising treatment strategy through sequential anti-inflammatory and pro-osteogenic effects for infectious bone-defect diseases.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122899"},"PeriodicalIF":12.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1016/j.biomaterials.2024.122875
Feilong Zhao , Zhibo Jia , Liyang Zhang , Guodong Liu , Junfei Li , Jianming Zhao , Yajie Xie , Lu Chen , Hongyu Jiang , Wei He , Aiyuan Wang , Jiang Peng , Yudong Zheng
The inflammatory microenvironment and inferior chondrogenesis are major symptoms after cartilage defect. Although various modifications strategies associated with hydrogels exhibit remarkable capacity of pro-cartilage regeneration, the adverse effect by prolonging inflammation is still formidable to hamper potential biomedical applications of different hydrogel implants. Herein, inspired by the repair microenvironment of articular cartilage defects, an injectable, immunomodulatory, and chondrogenic L-MNS-CMDA hydrogel is prepared through grafting vinyl and catechol groups to chitosan macromolecules using amide reaction, then further loading MnO2 nanosheets (MNS). The double crosslinking of photopolymerization and catechol oxidative polymerization endows L-MNS-CMDA hydrogel with preferable mechanical property, affording a suitable mechanical support for cartilage defect repair. Additionally, the robust tissue adhesion capability stemming from catechol groups guarantees the long-term retention of the hydrogel in the defect site. Meanwhile, L-MNS-CMDA hydrogel decomposes exogenous and intracellular H2O2 into O2 and H2O, to effectively alleviate cellular oxidative stress caused by long-term hypoxia. Under the synergies of catechol groups and MNS, L-MNS-CMDA hydrogel not only inhibits macrophages polarizing into M1 phenotype, but encourages them turn into M2 phenotype, thereby, reconstructing an immunization friendly microenvironment to ultimately enhance cartilage regeneration. Predictably, the hydrogel markedly induces rat bone marrow mesenchymal stem cells differentiating into chondrocytes by expressing abundant glycosaminoglycan and type II collagen. A cartilage defect model of rat knee joint indicates that L-MNS-CMDA hydrogel visually regulate the early inflammatory response of post-implantation, and facilitate cartilage regeneration and recovery of joint function after 12 weeks of post-implantation. All in all, this multifunctional L-MNS-CMDA hydrogel exhibits superior immunomodulatory and chondrogenic properties, holding immense clinical potential in the treatment of cartilage defects.
{"title":"A MnO2 nanosheets doping double crosslinked hydrogel for cartilage defect repair through alleviating inflammation and guiding chondrogenic differentiation","authors":"Feilong Zhao , Zhibo Jia , Liyang Zhang , Guodong Liu , Junfei Li , Jianming Zhao , Yajie Xie , Lu Chen , Hongyu Jiang , Wei He , Aiyuan Wang , Jiang Peng , Yudong Zheng","doi":"10.1016/j.biomaterials.2024.122875","DOIUrl":"10.1016/j.biomaterials.2024.122875","url":null,"abstract":"<div><div>The inflammatory microenvironment and inferior chondrogenesis are major symptoms after cartilage defect. Although various modifications strategies associated with hydrogels exhibit remarkable capacity of pro-cartilage regeneration, the adverse effect by prolonging inflammation is still formidable to hamper potential biomedical applications of different hydrogel implants. Herein, inspired by the repair microenvironment of articular cartilage defects, an injectable, immunomodulatory, and chondrogenic L-MNS-CMDA hydrogel is prepared through grafting vinyl and catechol groups to chitosan macromolecules using amide reaction, then further loading MnO<sub>2</sub> nanosheets (MNS). The double crosslinking of photopolymerization and catechol oxidative polymerization endows L-MNS-CMDA hydrogel with preferable mechanical property, affording a suitable mechanical support for cartilage defect repair. Additionally, the robust tissue adhesion capability stemming from catechol groups guarantees the long-term retention of the hydrogel in the defect site. Meanwhile, L-MNS-CMDA hydrogel decomposes exogenous and intracellular H<sub>2</sub>O<sub>2</sub> into O<sub>2</sub> and H<sub>2</sub>O, to effectively alleviate cellular oxidative stress caused by long-term hypoxia. Under the synergies of catechol groups and MNS, L-MNS-CMDA hydrogel not only inhibits macrophages polarizing into M1 phenotype, but encourages them turn into M2 phenotype, thereby, reconstructing an immunization friendly microenvironment to ultimately enhance cartilage regeneration. Predictably, the hydrogel markedly induces rat bone marrow mesenchymal stem cells differentiating into chondrocytes by expressing abundant glycosaminoglycan and type II collagen. A cartilage defect model of rat knee joint indicates that L-MNS-CMDA hydrogel visually regulate the early inflammatory response of post-implantation, and facilitate cartilage regeneration and recovery of joint function after 12 weeks of post-implantation. All in all, this multifunctional L-MNS-CMDA hydrogel exhibits superior immunomodulatory and chondrogenic properties, holding immense clinical potential in the treatment of cartilage defects.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122875"},"PeriodicalIF":12.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1016/j.biomaterials.2024.122898
Kyun Yoo Chi , Gyeongmin Kim , Hyojin Kim , Hyemin Kim , Seongyea Jo , Jihun Lee , Youngseok Lee , Heeseok Yoon , Seunghyun Cho , Jeongjun Kim , Jin-Seok Lee , Gyu-Bum Yeon , Dae-Sung Kim , Han-Jin Park , Jong-Hoon Kim
Hepatic organoids (HOs), primarily composed of hepatobiliary cells, do not represent the pathogenesis of liver diseases due to the lack of non-parenchymal cells. Multi-lineage liver organoids (mLOs) containing various cell types found in the liver offer a promising in vitro disease model. However, their structural complexity remains challenging to achieve due to the difficulty in optimizing culture conditions that meet the growth need of all component cell types. Here, we demonstrate that cystic HOs generated from hPSCs can be expanded long-term and serve as a continuous source for generating complex mLOs. Assembling cystic HOs with hPSC-derived endothelial and hepatic stellate cell-like cells under conventional HO culture conditions failed to support the development of multiple cell types within mLOs, resulting in biased differentiation towards specific cell types. In contrast, modulating the cAMP/Wnt/Hippo signaling pathways with small molecules during assembly and differentiation phases efficiently generate mLOs containing both hepatic parenchymal and non-parenchymal cells. These mLOs exhibited structural complexity and functional maturity, including vascular network formation between parenchymal lobular structures, cell polarity for bile secretion, and the capacity to respond to fibrotic stimuli. Our study underscores the importance of modulating signaling pathways to enhance mLO structural complexity for applications in modeling liver pathologies.
肝脏器质性组织(HOs)主要由肝胆细胞组成,由于缺乏非实质性细胞,因此不能代表肝脏疾病的发病机制。多线肝脏器官组织(mLO)包含肝脏中的各种细胞类型,是一种很有前景的体外疾病模型。然而,由于难以优化培养条件以满足所有组成细胞类型的生长需要,要实现其结构的复杂性仍然具有挑战性。在这里,我们证明了由 hPSCs 生成的囊性 HOs 可以长期扩增,并可作为生成复杂 mLOs 的持续来源。在传统的 HO 培养条件下,用 hPSC 衍生的内皮细胞和肝星状细胞样细胞组装囊性 HO 无法支持 mLO 内多种细胞类型的发育,导致细胞偏向于特定类型的分化。与此相反,在组装和分化阶段用小分子调节cAMP/Wnt/Hippo信号通路,可有效生成包含肝实质细胞和非肝实质细胞的mLO。这些mLO表现出结构的复杂性和功能的成熟性,包括实质小叶结构之间血管网络的形成、胆汁分泌的细胞极性以及对纤维化刺激做出反应的能力。我们的研究强调了调节信号通路以增强mLO结构复杂性在肝脏病理建模中应用的重要性。
{"title":"Optimization of culture conditions to generate vascularized multi-lineage liver organoids with structural complexity and functionality","authors":"Kyun Yoo Chi , Gyeongmin Kim , Hyojin Kim , Hyemin Kim , Seongyea Jo , Jihun Lee , Youngseok Lee , Heeseok Yoon , Seunghyun Cho , Jeongjun Kim , Jin-Seok Lee , Gyu-Bum Yeon , Dae-Sung Kim , Han-Jin Park , Jong-Hoon Kim","doi":"10.1016/j.biomaterials.2024.122898","DOIUrl":"10.1016/j.biomaterials.2024.122898","url":null,"abstract":"<div><div>Hepatic organoids (HOs), primarily composed of hepatobiliary cells, do not represent the pathogenesis of liver diseases due to the lack of non-parenchymal cells. Multi-lineage liver organoids (mLOs) containing various cell types found in the liver offer a promising <em>in vitro</em> disease model. However, their structural complexity remains challenging to achieve due to the difficulty in optimizing culture conditions that meet the growth need of all component cell types. Here, we demonstrate that cystic HOs generated from hPSCs can be expanded long-term and serve as a continuous source for generating complex mLOs. Assembling cystic HOs with hPSC-derived endothelial and hepatic stellate cell-like cells under conventional HO culture conditions failed to support the development of multiple cell types within mLOs, resulting in biased differentiation towards specific cell types. In contrast, modulating the cAMP/Wnt/Hippo signaling pathways with small molecules during assembly and differentiation phases efficiently generate mLOs containing both hepatic parenchymal and non-parenchymal cells. These mLOs exhibited structural complexity and functional maturity, including vascular network formation between parenchymal lobular structures, cell polarity for bile secretion, and the capacity to respond to fibrotic stimuli. Our study underscores the importance of modulating signaling pathways to enhance mLO structural complexity for applications in modeling liver pathologies.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122898"},"PeriodicalIF":12.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-16DOI: 10.1016/j.biomaterials.2024.122896
Hong Lyun Kim , Gurusamy Saravanakumar , Seowon Lee , Subin Jang , Seonwoo Kang , Mihyeon Park , Sivasangu Sobha , So-Hee Park , Soo-Min Kim , Jung-Ah Lee , Eunkyung Shin , You-jin Kim , Hye-Sook Jeong , Dokeun Kim , Won Jong Kim
Non-viral vectors for mRNA delivery primarily include lipid nanoparticles (LNPs) and polymers. While LNPs are known for their high mRNA delivery efficiency, they can induce excessive immune responses and cause off-target effects, potentially leading to side effects. In this study, we aimed to explore polymer-based mRNA delivery systems as a viable alternative to LNPs, focusing on their mRNA delivery efficiency and potential application in mRNA vaccines. We created a library of poly(β-amino ester) (PBAE) polymers by combining various amine monomers and acrylate monomers. Through screening this polymer library, we identified specific polymer nanoparticles (PNPs) that demonstrated high mRNA expression efficiency, with sustained mRNA expression for up to two weeks. Furthermore, the PNPs showed mRNA expression only at the injection site and did not exhibit liver toxicity. Additionally, when assessing immune activation, the PNPs significantly induced T-cell immune activation and were effective in the plaque reduction neutralization test. These results suggest that polymer-based mRNA delivery systems not only hold potential for use in mRNA vaccines but also show promise for therapeutic applications.
{"title":"Poly(β-amino ester) polymer library with monomer variation for mRNA delivery","authors":"Hong Lyun Kim , Gurusamy Saravanakumar , Seowon Lee , Subin Jang , Seonwoo Kang , Mihyeon Park , Sivasangu Sobha , So-Hee Park , Soo-Min Kim , Jung-Ah Lee , Eunkyung Shin , You-jin Kim , Hye-Sook Jeong , Dokeun Kim , Won Jong Kim","doi":"10.1016/j.biomaterials.2024.122896","DOIUrl":"10.1016/j.biomaterials.2024.122896","url":null,"abstract":"<div><div>Non-viral vectors for mRNA delivery primarily include lipid nanoparticles (LNPs) and polymers. While LNPs are known for their high mRNA delivery efficiency, they can induce excessive immune responses and cause off-target effects, potentially leading to side effects. In this study, we aimed to explore polymer-based mRNA delivery systems as a viable alternative to LNPs, focusing on their mRNA delivery efficiency and potential application in mRNA vaccines. We created a library of poly(β-amino ester) (PBAE) polymers by combining various amine monomers and acrylate monomers. Through screening this polymer library, we identified specific polymer nanoparticles (PNPs) that demonstrated high mRNA expression efficiency, with sustained mRNA expression for up to two weeks. Furthermore, the PNPs showed mRNA expression only at the injection site and did not exhibit liver toxicity. Additionally, when assessing immune activation, the PNPs significantly induced T-cell immune activation and were effective in the plaque reduction neutralization test. These results suggest that polymer-based mRNA delivery systems not only hold potential for use in mRNA vaccines but also show promise for therapeutic applications.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122896"},"PeriodicalIF":12.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-16DOI: 10.1016/j.biomaterials.2024.122890
Kun Wang , Yu Sun , Ke Zhu , Yiqiong Liu , Xiao Zheng , Zichen Yang , Fulong Man , Li Huang , Ziyang Zhu , Qi Huang , Yan Li , Haiqing Dong , Jun Zhao , Yongyong Li
Pyroptosis is a critical pathological mechanism implicated in myocardial damage following myocardial infarction (MI), and the crosstalk between macrophages and pyroptotic cardiomyocytes presents a formidable challenge for anti-pyroptosis therapies of MI. However, as single-target pyroptosis inhibitors frequently fail to address this crosstalk, the efficacy of anti-pyroptosis treatment post-MI remains inadequate. Therefore, the exploration of more potent anti-pyroptosis approaches is imperative for improving outcomes in MI treatment, particularly in addressing the crosstalk between macrophages and pyroptotic cardiomyocytes. Here, in response to this crosstalk, we engineered an anti-pyroptosis biomimetic nanoplatform (NM@PDA@PU), employing polydopamine (PDA) nanoparticles enveloped with neutrophil membrane (NM) for targeted delivery of puerarin (PU). Notably, network pharmacology is deployed to discern the most efficacious anti-pyroptosis drug (puerarin) among the 7 primary active monomers of TCM formulations widely applied in clinical practice and reveal the effect of puerarin on the crosstalk. Additionally, targeted delivery of puerarin could disrupt the malignant crosstalk between macrophages and pyroptotic cardiomyocytes, and enhance the effect of anti-pyroptosis by not only directly inhibiting cardiomyocytes pyroptosis through NLRP3-CASP1-IL-1β/IL-18 signal pathway, but reshaping the inflammatory microenvironment by reprogramming macrophages to anti-inflammatory M2 subtype. Overall, NM@PDA@PU could enhance anti-pyroptosis effect by disrupting the crosstalk between M1 macrophages and pyroptotic cardiomyocytes to protect cardiomyocytes, ameliorate cardiac function and improve ventricular remodeling, which providing new insights for the efficient treatment of MI.
{"title":"Anti-pyroptosis biomimetic nanoplatform loading puerarin for myocardial infarction repair: From drug discovery to drug delivery","authors":"Kun Wang , Yu Sun , Ke Zhu , Yiqiong Liu , Xiao Zheng , Zichen Yang , Fulong Man , Li Huang , Ziyang Zhu , Qi Huang , Yan Li , Haiqing Dong , Jun Zhao , Yongyong Li","doi":"10.1016/j.biomaterials.2024.122890","DOIUrl":"10.1016/j.biomaterials.2024.122890","url":null,"abstract":"<div><div>Pyroptosis is a critical pathological mechanism implicated in myocardial damage following myocardial infarction (MI), and the crosstalk between macrophages and pyroptotic cardiomyocytes presents a formidable challenge for anti-pyroptosis therapies of MI. However, as single-target pyroptosis inhibitors frequently fail to address this crosstalk, the efficacy of anti-pyroptosis treatment post-MI remains inadequate. Therefore, the exploration of more potent anti-pyroptosis approaches is imperative for improving outcomes in MI treatment, particularly in addressing the crosstalk between macrophages and pyroptotic cardiomyocytes. Here, in response to this crosstalk, we engineered an anti-pyroptosis biomimetic nanoplatform (NM@PDA@PU), employing polydopamine (PDA) nanoparticles enveloped with neutrophil membrane (NM) for targeted delivery of puerarin (PU). Notably, network pharmacology is deployed to discern the most efficacious anti-pyroptosis drug (puerarin) among the 7 primary active monomers of TCM formulations widely applied in clinical practice and reveal the effect of puerarin on the crosstalk. Additionally, targeted delivery of puerarin could disrupt the malignant crosstalk between macrophages and pyroptotic cardiomyocytes, and enhance the effect of anti-pyroptosis by not only directly inhibiting cardiomyocytes pyroptosis through NLRP3-CASP1-IL-1β/IL-18 signal pathway, but reshaping the inflammatory microenvironment by reprogramming macrophages to anti-inflammatory M2 subtype. Overall, NM@PDA@PU could enhance anti-pyroptosis effect by disrupting the crosstalk between M1 macrophages and pyroptotic cardiomyocytes to protect cardiomyocytes, ameliorate cardiac function and improve ventricular remodeling, which providing new insights for the efficient treatment of MI.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122890"},"PeriodicalIF":12.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-16DOI: 10.1016/j.biomaterials.2024.122897
Yuanyuan Guo , Fujun Wang , Sunli Wan , Xinhua Liu , Yu Huang , Miao Xie , Xiaoer Wei , Wangshu Zhu , Tingting Yao , Yuehua Li , Chuan Zhang , Yueqi Zhu
Atherosclerosis-induced lethal cardiovascular disease remains a severe healthcare threat due to the limited drug efficiency and untimely prediction of high-risk events caused by inadequate target specificity of medications, incapable recognition of insensitive patients, and variable morphology of vulnerable plaques. Therefore, it is necessary to develop efficient strategies to improve the diagnosis accuracy and achieve visualized treatment of atherosclerosis. Herein, we establish an inflamed endothelium-targeted three-in-one nucleic acid nanogel system that can reverse the inflammatory state of endothelial cells (ECs) in plaques and simultaneously achieve real-time monitoring of the therapy process for efficient atherosclerosis diagnosis and treatment. For this purpose, contrast agent (Gd-DOTA) and VCAM-1-targeted peptide (VP) are first covalently conjugated onto DNA strands by click reaction respectively, which could self-assemble into Y-shaped structures (Gd-Y1 and VP-Y2 motifs) with magnetic resonance (MR) imaging and endothelium targeting capacities. Thereafter, NF-κB subunit p65-targeting siRNA (siNF-κB) is crosslinked with Gd-Y1 and VP-Y2 motifs to construct the endothelium-targeting nanogel platform. With contrast agents inside, the nanogel enables MR-based diagnosis and visualized therapy of atherosclerosis, providing accurate prognostic analysis and indications for treatment results, which ensures timely disclosure of insensitive individuals and avoids acute lethal events. By delivering siNF-κB to inflammatory endothelium, the nanogel significantly regresses plaques in both the aorta and carotid artery with reduced inflammation cytokines, collagens, macrophages, and apoptotic cells, providing a potential anti-inflammation strategy to treat atherosclerosis and avoid acute cardiovascular disease.
由于药物的靶向特异性不足、无法识别不敏感患者以及易损斑块的形态多变,导致药物疗效有限且无法及时预测高危事件,动脉粥样硬化引发的致命性心血管疾病仍是严重的医疗威胁。因此,有必要开发有效的策略来提高诊断的准确性,实现动脉粥样硬化的可视化治疗。在此,我们建立了一种以炎症内皮细胞为靶点的三合一核酸纳米凝胶系统,它能逆转斑块中内皮细胞(EC)的炎症状态,同时实现对治疗过程的实时监控,从而达到高效诊断和治疗动脉粥样硬化的目的。为此,首先通过点击反应将造影剂(Gd-DOTA)和 VCAM-1 靶向肽(VP)分别共价键合到 DNA 链上,从而自组装成具有磁共振(MR)成像和内皮靶向能力的 Y 型结构(Gd-Y1 和 VP-Y2 motifs)。随后,NF-κB 亚基 p65 靶向 siRNA(siNF-κB)与 Gd-Y1 和 VP-Y2 基团交联,构建内皮靶向纳米凝胶平台。该纳米凝胶内含造影剂,可对动脉粥样硬化进行基于磁共振的诊断和可视化治疗,提供准确的预后分析和治疗结果指示,确保及时披露不敏感人群,避免急性致死事件的发生。通过向炎症内皮细胞递送 siNF-κB,纳米凝胶能显著消退主动脉和颈动脉的斑块,减少炎症细胞因子、胶原蛋白、巨噬细胞和凋亡细胞,为治疗动脉粥样硬化和避免急性心血管疾病提供了一种潜在的抗炎策略。
{"title":"Endothelium-targeted NF-κB siRNA nanogel for magnetic resonance imaging and visualized-anti-inflammation treatment of atherosclerosis","authors":"Yuanyuan Guo , Fujun Wang , Sunli Wan , Xinhua Liu , Yu Huang , Miao Xie , Xiaoer Wei , Wangshu Zhu , Tingting Yao , Yuehua Li , Chuan Zhang , Yueqi Zhu","doi":"10.1016/j.biomaterials.2024.122897","DOIUrl":"10.1016/j.biomaterials.2024.122897","url":null,"abstract":"<div><div>Atherosclerosis-induced lethal cardiovascular disease remains a severe healthcare threat due to the limited drug efficiency and untimely prediction of high-risk events caused by inadequate target specificity of medications, incapable recognition of insensitive patients, and variable morphology of vulnerable plaques. Therefore, it is necessary to develop efficient strategies to improve the diagnosis accuracy and achieve visualized treatment of atherosclerosis. Herein, we establish an inflamed endothelium-targeted three-in-one nucleic acid nanogel system that can reverse the inflammatory state of endothelial cells (ECs) in plaques and simultaneously achieve real-time monitoring of the therapy process for efficient atherosclerosis diagnosis and treatment. For this purpose, contrast agent (Gd-DOTA) and VCAM-1-targeted peptide (VP) are first covalently conjugated onto DNA strands by click reaction respectively, which could self-assemble into Y-shaped structures (Gd-Y1 and VP-Y2 motifs) with magnetic resonance (MR) imaging and endothelium targeting capacities. Thereafter, NF-κB subunit p65-targeting siRNA (siNF-κB) is crosslinked with Gd-Y1 and VP-Y2 motifs to construct the endothelium-targeting nanogel platform. With contrast agents inside, the nanogel enables MR-based diagnosis and visualized therapy of atherosclerosis, providing accurate prognostic analysis and indications for treatment results, which ensures timely disclosure of insensitive individuals and avoids acute lethal events. By delivering siNF-κB to inflammatory endothelium, the nanogel significantly regresses plaques in both the aorta and carotid artery with reduced inflammation cytokines, collagens, macrophages, and apoptotic cells, providing a potential anti-inflammation strategy to treat atherosclerosis and avoid acute cardiovascular disease.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122897"},"PeriodicalIF":12.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-15DOI: 10.1016/j.biomaterials.2024.122892
Jie Jiang , Yuhao Lu , Xinyi Zheng , Maomao Xie , Aleksandra Jauković , Meng Gao , Huizhen Zheng
Disruption of redox homeostasis profoundly affects cellular metabolism and activities. While oxidative stress is extensively studied in cancer therapies, research on reductive stress remains in its infancy. Molecular hydrogen (H2), a well-known antioxidant, holds significant potential to induce reductive stress due to its strong antioxidative properties, making it a promising candidate for cancer therapy. However, it remains a major challenge to develop a sustainable H2 delivery system in vivo. Herein, we designed a micro-factory by engineering a gel-based microcapsule that encapsulates Enterobacter aerogenes, a.k.a. probiotic biohydrogen microcapsules (PBMCs), enabling the sustained H2 generation within tumor microenvironment. Notably, PBMCs effectively suppressed the proliferation of eight tumor cell lines as well as drug-resistant cancer cells. The prolonged H2 release from PBMCs induced reductive stress, as evidenced by a significant increase in the GSH/GSSG ratio in 4T1 cells. Moreover, PBMCs displayed significant antitumor effects in breast, melanoma and liver cancer models. The inhibition of PI3K-AKT pathway and the activation of MAPK pathway were identified as key mechanisms responsible for inducing tumor cell cycle arrest and apoptosis. The PBMCs also exhibited synergistic effects in combination with chemotherapeutics, resulting in robust inhibitions of preinvasive carcinoma growth and commonly associated pulmonary metastasis. Overall, our study introduces an innovative strategy to manipulate reductive stress in the tumor microenvironment through in situ H2 generation, thereby enhancing tumor vulnerability.
{"title":"Engineering probiotic biohydrogen micro-factories to initiate reductive stress for boosting tumor vulnerability","authors":"Jie Jiang , Yuhao Lu , Xinyi Zheng , Maomao Xie , Aleksandra Jauković , Meng Gao , Huizhen Zheng","doi":"10.1016/j.biomaterials.2024.122892","DOIUrl":"10.1016/j.biomaterials.2024.122892","url":null,"abstract":"<div><div>Disruption of redox homeostasis profoundly affects cellular metabolism and activities. While oxidative stress is extensively studied in cancer therapies, research on reductive stress remains in its infancy. Molecular hydrogen (H<sub>2</sub>), a well-known antioxidant, holds significant potential to induce reductive stress due to its strong antioxidative properties, making it a promising candidate for cancer therapy. However, it remains a major challenge to develop a sustainable H<sub>2</sub> delivery system <em>in vivo</em>. Herein, we designed a micro-factory by engineering a gel-based microcapsule that encapsulates <em>Enterobacter aerogenes</em>, <em>a.k.a</em>. probiotic biohydrogen microcapsules (PBMCs), enabling the sustained H<sub>2</sub> generation within tumor microenvironment. Notably, PBMCs effectively suppressed the proliferation of eight tumor cell lines as well as drug-resistant cancer cells. The prolonged H<sub>2</sub> release from PBMCs induced reductive stress, as evidenced by a significant increase in the GSH/GSSG ratio in 4T1 cells. Moreover, PBMCs displayed significant antitumor effects in breast, melanoma and liver cancer models. The inhibition of PI3K-AKT pathway and the activation of MAPK pathway were identified as key mechanisms responsible for inducing tumor cell cycle arrest and apoptosis. The PBMCs also exhibited synergistic effects in combination with chemotherapeutics, resulting in robust inhibitions of preinvasive carcinoma growth and commonly associated pulmonary metastasis. Overall, our study introduces an innovative strategy to manipulate reductive stress in the tumor microenvironment through <em>in situ</em> H<sub>2</sub> generation, thereby enhancing tumor vulnerability.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122892"},"PeriodicalIF":12.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vascular pathologies and injuries are important factors for the delayed wound healing in diabetes. Previous studies have demonstrated that hypoxic environments could induce formation of new blood vessels by regulating intercellular communication and cellular behaviors. In this study, we have enhanced the angiogenic potential of exosomes by subjecting urine-derived stem cells (USCs) to hypoxic preconditioning. To prolong the retention of exosomes at the wound site, we have also engineered a novel dECM hydrogel termed SISMA, which was modified from porcine small intestinal submucosa (SIS). For its rapid and controllable gelation kinetics, excellent biocompatibility, and exosome release capability, the SISMA hydrogel has proven to be a reliable delivery vehicle for exosomes. The hypoxia-induced exosomes-loaded hydrogel has promoted endothelial cell proliferation, migration, and tube formation. More importantly, as evidenced by significant in vivo vascular regeneration in the early stages post-injury, it has facilitated tissue repair. This may because miR-486–5p in H-exo inhibit SERPINE1 activity in endothelial cell. Additionally, miRNA sequencing analysis suggested that the underlying mechanism for enhanced angiogenesis may be associated with the activation of classical HIF-1α signaling pathway. In summary, our study has presented a novel non-invasive, cell-free therapeutic approach for accelerating diabetes wound healing and development of a practical and efficient exosomes delivery platform.
{"title":"Exosomes from hypoxic urine-derived stem cells facilitate healing of diabetic wound by targeting SERPINE1 through miR-486-5p","authors":"Ming-Hui Fan , Xiu-Zhen Zhang , Yan-Lin Jiang , Jin-Kui Pi , Ji-Ye Zhang , Yue-Qi Zhang , Fei Xing , Hui-Qi Xie","doi":"10.1016/j.biomaterials.2024.122893","DOIUrl":"10.1016/j.biomaterials.2024.122893","url":null,"abstract":"<div><div>Vascular pathologies and injuries are important factors for the delayed wound healing in diabetes. Previous studies have demonstrated that hypoxic environments could induce formation of new blood vessels by regulating intercellular communication and cellular behaviors. In this study, we have enhanced the angiogenic potential of exosomes by subjecting urine-derived stem cells (USCs) to hypoxic preconditioning. To prolong the retention of exosomes at the wound site, we have also engineered a novel dECM hydrogel termed SISMA, which was modified from porcine small intestinal submucosa (SIS). For its rapid and controllable gelation kinetics, excellent biocompatibility, and exosome release capability, the SISMA hydrogel has proven to be a reliable delivery vehicle for exosomes. The hypoxia-induced exosomes-loaded hydrogel has promoted endothelial cell proliferation, migration, and tube formation. More importantly, as evidenced by significant <em>in vivo</em> vascular regeneration in the early stages post-injury, it has facilitated tissue repair. This may because miR-486–5p in H-exo inhibit <em>SERPINE1</em> activity in endothelial cell. Additionally, miRNA sequencing analysis suggested that the underlying mechanism for enhanced angiogenesis may be associated with the activation of classical HIF-1α signaling pathway. In summary, our study has presented a novel non-invasive, cell-free therapeutic approach for accelerating diabetes wound healing and development of a practical and efficient exosomes delivery platform.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122893"},"PeriodicalIF":12.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-13DOI: 10.1016/j.biomaterials.2024.122881
Wenbo Gao , Xiaoning Zhang , Wenhui Hu , Jie Han , Xiaoheng Liu , Yan Zhang , Mian Long
Substrate anchorage is essential for cell migration, and actin polymerization at cell front and myosin contractility at cell rear are known to govern cell forward movement. Yet their differential driving strategies for neutrophil migration on distinct adhesiveness substrates and their contributions to the migration-induced trail formation remain unclear. Here we explore the morphological changes, migration dynamics, and trail formation of neutrophils on ICAM-1 and PLL substrates, with a focus on the relationships among adhesive forces, traction forces, and out-of-plane forces. Results indicate that, on ICAM-1, neutrophil migration and trail formation rely on the coordinated interactions of Arp2/3 and myosin, along with biochemical regulation (via Syk and calpain) of adhesion and de-adhesion. This pattern leads to traction forces being concentrated at relatively fewer adhesive sites, facilitating cell forward migration. On PLL, however, neutrophils primarily depend on Arp2/3-mediated actin polymerization, resulting in a broader distribution of traction forces and weaker adhesions, which allows for higher leading-edge migrating velocities. Elevated membrane tension and out-of-plane forces generated by bleb protrusions on PLL reduce the reliance on myosin-driven contraction at the trailing edge, enabling easier tail detachment through elastic recoil. This work highlights the differential impact of substrate adhesiveness on neutrophil migration and trail formation and dynamics, providing new insights into cell migration mechanisms and potential therapeutic targets for inflammatory and immune-related disorders.
{"title":"Neutrophils exhibit flexible migration strategies and trail formation mechanisms on varying adhesive substrates","authors":"Wenbo Gao , Xiaoning Zhang , Wenhui Hu , Jie Han , Xiaoheng Liu , Yan Zhang , Mian Long","doi":"10.1016/j.biomaterials.2024.122881","DOIUrl":"10.1016/j.biomaterials.2024.122881","url":null,"abstract":"<div><div>Substrate anchorage is essential for cell migration, and actin polymerization at cell front and myosin contractility at cell rear are known to govern cell forward movement. Yet their differential driving strategies for neutrophil migration on distinct adhesiveness substrates and their contributions to the migration-induced trail formation remain unclear. Here we explore the morphological changes, migration dynamics, and trail formation of neutrophils on ICAM-1 and PLL substrates, with a focus on the relationships among adhesive forces, traction forces, and out-of-plane forces. Results indicate that, on ICAM-1, neutrophil migration and trail formation rely on the coordinated interactions of Arp2/3 and myosin, along with biochemical regulation (<em>via</em> Syk and calpain) of adhesion and de-adhesion. This pattern leads to traction forces being concentrated at relatively fewer adhesive sites, facilitating cell forward migration. On PLL, however, neutrophils primarily depend on Arp2/3-mediated actin polymerization, resulting in a broader distribution of traction forces and weaker adhesions, which allows for higher leading-edge migrating velocities. Elevated membrane tension and out-of-plane forces generated by bleb protrusions on PLL reduce the reliance on myosin-driven contraction at the trailing edge, enabling easier tail detachment through elastic recoil. This work highlights the differential impact of substrate adhesiveness on neutrophil migration and trail formation and dynamics, providing new insights into cell migration mechanisms and potential therapeutic targets for inflammatory and immune-related disorders.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122881"},"PeriodicalIF":12.8,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}