Yue Wang , Jun Liu , Hongyan Cui , Liuwei Zhang , Zhen Li , Xiumei Wang , Jing Wang , Qixian Chen , Yan Zhao
{"title":"三重可转换动态环境,用于生物脆弱 mRNA 有效载荷的程序化运输,以系统治疗难治性实体瘤。","authors":"Yue Wang , Jun Liu , Hongyan Cui , Liuwei Zhang , Zhen Li , Xiumei Wang , Jing Wang , Qixian Chen , Yan Zhao","doi":"10.1016/j.biomaterials.2024.122677","DOIUrl":null,"url":null,"abstract":"<div><p>The surface physiochemical properties of nanomedicine play a crucial role in modulating biointerfacial reactions in sequential biological compartments, accordingly accomplishing the desired programmed delivery scenario to intracellular targets. PEGylation, which involves modifying the surface with a layer of poly(ethylene glycol), has been validated as an effective strategy for minimizing adverse biointerfacial interactions. However, it has also been observed to impede cellular uptake and intracellular trafficking activities. To address this dilemma, we propose a dynamic surface chemistry approach that actively prevents non-specific reactions in systemic circulation, while readily facilitating cellular uptake by converting into a highly cytomembrane-adhesive state. Moreover, the surface becomes more adhesive to endolysosomal membranes, enabling translocation into the cytosol. In this study, PEGylated mRNA delivery nanoparticulates were tethered with charge-reversible polymers to create dynamic surroundings through click chemistry. Importantly, the dynamic surroundings exhibited negative charges under physiological conditions (pH 7.4). This property prevented degradation by anionic nucleases and structural disassembly induced by endogenous charged biological species. Consequently, the nanoparticles exhibited appreciable stealth function, effectively managing the first pass effect, leading to prolonged blood retention and improved bioavailabilities at targeted cells. Furthermore, the dynamic surroundings shifted towards relatively positive charges in the tumor microenvironment (pH 6.8). As a result, the nanoparticles were more likely to be taken up by tumors due to their electrostatic affinities towards polyanionic cytomembranes. Eventually, the internalized mRNA nanomedicine transformed responsive to the surrounding microenvironment into highly positive charges within acidic endolysosomes (pH 5.0), exerting explosive disruptive potencies on the endolysosomal structures, thus facilitating translocation of mRNA from the digestive endolysosomes into the targeted cytosol. Notably, the dynamic surroundings also reduced the immunogenicity of naked mRNA due to their stealthy properties and rapid endolysosomal translocation functions. In summary, our proposed unique triple-transformable dynamic surface chemistry provided an intriguing delivery scenario that overcomes sequential biological barriers, contributing to efficient expression of the encapsulated mRNA at targeted tumors.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8000,"publicationDate":"2024-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Triple-transformable dynamic surroundings for programmed transportation of bio-vulnerable mRNA payloads towards systemic treatment of intractable solid tumors\",\"authors\":\"Yue Wang , Jun Liu , Hongyan Cui , Liuwei Zhang , Zhen Li , Xiumei Wang , Jing Wang , Qixian Chen , Yan Zhao\",\"doi\":\"10.1016/j.biomaterials.2024.122677\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The surface physiochemical properties of nanomedicine play a crucial role in modulating biointerfacial reactions in sequential biological compartments, accordingly accomplishing the desired programmed delivery scenario to intracellular targets. PEGylation, which involves modifying the surface with a layer of poly(ethylene glycol), has been validated as an effective strategy for minimizing adverse biointerfacial interactions. However, it has also been observed to impede cellular uptake and intracellular trafficking activities. To address this dilemma, we propose a dynamic surface chemistry approach that actively prevents non-specific reactions in systemic circulation, while readily facilitating cellular uptake by converting into a highly cytomembrane-adhesive state. Moreover, the surface becomes more adhesive to endolysosomal membranes, enabling translocation into the cytosol. In this study, PEGylated mRNA delivery nanoparticulates were tethered with charge-reversible polymers to create dynamic surroundings through click chemistry. Importantly, the dynamic surroundings exhibited negative charges under physiological conditions (pH 7.4). This property prevented degradation by anionic nucleases and structural disassembly induced by endogenous charged biological species. Consequently, the nanoparticles exhibited appreciable stealth function, effectively managing the first pass effect, leading to prolonged blood retention and improved bioavailabilities at targeted cells. Furthermore, the dynamic surroundings shifted towards relatively positive charges in the tumor microenvironment (pH 6.8). As a result, the nanoparticles were more likely to be taken up by tumors due to their electrostatic affinities towards polyanionic cytomembranes. Eventually, the internalized mRNA nanomedicine transformed responsive to the surrounding microenvironment into highly positive charges within acidic endolysosomes (pH 5.0), exerting explosive disruptive potencies on the endolysosomal structures, thus facilitating translocation of mRNA from the digestive endolysosomes into the targeted cytosol. Notably, the dynamic surroundings also reduced the immunogenicity of naked mRNA due to their stealthy properties and rapid endolysosomal translocation functions. In summary, our proposed unique triple-transformable dynamic surface chemistry provided an intriguing delivery scenario that overcomes sequential biological barriers, contributing to efficient expression of the encapsulated mRNA at targeted tumors.</p></div>\",\"PeriodicalId\":254,\"journal\":{\"name\":\"Biomaterials\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2024-06-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biomaterials\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0142961224002114\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENGINEERING, BIOMEDICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomaterials","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0142961224002114","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}
Triple-transformable dynamic surroundings for programmed transportation of bio-vulnerable mRNA payloads towards systemic treatment of intractable solid tumors
The surface physiochemical properties of nanomedicine play a crucial role in modulating biointerfacial reactions in sequential biological compartments, accordingly accomplishing the desired programmed delivery scenario to intracellular targets. PEGylation, which involves modifying the surface with a layer of poly(ethylene glycol), has been validated as an effective strategy for minimizing adverse biointerfacial interactions. However, it has also been observed to impede cellular uptake and intracellular trafficking activities. To address this dilemma, we propose a dynamic surface chemistry approach that actively prevents non-specific reactions in systemic circulation, while readily facilitating cellular uptake by converting into a highly cytomembrane-adhesive state. Moreover, the surface becomes more adhesive to endolysosomal membranes, enabling translocation into the cytosol. In this study, PEGylated mRNA delivery nanoparticulates were tethered with charge-reversible polymers to create dynamic surroundings through click chemistry. Importantly, the dynamic surroundings exhibited negative charges under physiological conditions (pH 7.4). This property prevented degradation by anionic nucleases and structural disassembly induced by endogenous charged biological species. Consequently, the nanoparticles exhibited appreciable stealth function, effectively managing the first pass effect, leading to prolonged blood retention and improved bioavailabilities at targeted cells. Furthermore, the dynamic surroundings shifted towards relatively positive charges in the tumor microenvironment (pH 6.8). As a result, the nanoparticles were more likely to be taken up by tumors due to their electrostatic affinities towards polyanionic cytomembranes. Eventually, the internalized mRNA nanomedicine transformed responsive to the surrounding microenvironment into highly positive charges within acidic endolysosomes (pH 5.0), exerting explosive disruptive potencies on the endolysosomal structures, thus facilitating translocation of mRNA from the digestive endolysosomes into the targeted cytosol. Notably, the dynamic surroundings also reduced the immunogenicity of naked mRNA due to their stealthy properties and rapid endolysosomal translocation functions. In summary, our proposed unique triple-transformable dynamic surface chemistry provided an intriguing delivery scenario that overcomes sequential biological barriers, contributing to efficient expression of the encapsulated mRNA at targeted tumors.
期刊介绍:
Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.