Ruowen Sun , Yanchao Yang , Bin Zhang , Jiayuan Chen , Ye Wang , Zehui Jiang , Linlin Zhang , Milad Ashrafizadeh , Gautam Sethi , Jing Shen , Zuofei Chi
{"title":"肿瘤归巢外泌体能够靶向递送siRNA和异欧前胡素,以克服DLBCL中BTK抑制剂的耐药性","authors":"Ruowen Sun , Yanchao Yang , Bin Zhang , Jiayuan Chen , Ye Wang , Zehui Jiang , Linlin Zhang , Milad Ashrafizadeh , Gautam Sethi , Jing Shen , Zuofei Chi","doi":"10.1016/j.mtbio.2025.102267","DOIUrl":null,"url":null,"abstract":"<div><div>Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, but over one-third of patients relapse or develop refractory disease after first-line therapy. Novel therapeutic strategies are required to address persistent unmet clinical needs for DLBCL. This study aimed to develop an exosome-based drug delivery system for the targeted combination therapy of siRNA against Bruton's tyrosine kinase (BTK, an established therapeutic target in B cell lymphomas) and isoimperatorin (ISOIM, an active natural furanocoumarin showing anti-tumor effects) in DLBCL. Tumor exosomes were isolated as the delivery carrier. ISOIM/siBTK@Exosome was prepared by encapsulating ISOIM and si-BTK into exosome using electroporation. Cellular uptake, immune escape, targeted delivery efficiency, anti-lymphoma activity and biosafety of ISOIM/siBTK@Exosome were evaluated in two DLBCL cell lines and in tumor-bearing mice. ISOIM/siBTK@Exosome displayed significant anti-lymphoma activity compared to ISOIM@Exosome or siBTK@Exosome alone, demonstrating synergistic therapeutic role of ISOIM and si-BTK. Besides, ISOIM/siBTK@Exosome can accelerate T cells activation and prevent macrophage M2 polarization in vitro. Administration of ISOIM/siBTK@Exosome to tumor-bearing mice significantly inhibited tumor growth and prolonged survival. The ISOIM/siBTK@Exosome was biocompatible and biosafe in vivo without damage on the major organs in H&E staining. The prepared ISOIM/siBTK@Exosome may provide novel targeted therapeutic strategy to be applied in the clinical management of patients with DLBCL.</div></div>","PeriodicalId":18310,"journal":{"name":"Materials Today Bio","volume":"35 ","pages":"Article 102267"},"PeriodicalIF":10.2000,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tumor-homing exosomes enable targeted delivery of siRNA and isoimperatorin for overcoming BTK inhibitor resistance in DLBCL\",\"authors\":\"Ruowen Sun , Yanchao Yang , Bin Zhang , Jiayuan Chen , Ye Wang , Zehui Jiang , Linlin Zhang , Milad Ashrafizadeh , Gautam Sethi , Jing Shen , Zuofei Chi\",\"doi\":\"10.1016/j.mtbio.2025.102267\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, but over one-third of patients relapse or develop refractory disease after first-line therapy. Novel therapeutic strategies are required to address persistent unmet clinical needs for DLBCL. This study aimed to develop an exosome-based drug delivery system for the targeted combination therapy of siRNA against Bruton's tyrosine kinase (BTK, an established therapeutic target in B cell lymphomas) and isoimperatorin (ISOIM, an active natural furanocoumarin showing anti-tumor effects) in DLBCL. Tumor exosomes were isolated as the delivery carrier. ISOIM/siBTK@Exosome was prepared by encapsulating ISOIM and si-BTK into exosome using electroporation. Cellular uptake, immune escape, targeted delivery efficiency, anti-lymphoma activity and biosafety of ISOIM/siBTK@Exosome were evaluated in two DLBCL cell lines and in tumor-bearing mice. ISOIM/siBTK@Exosome displayed significant anti-lymphoma activity compared to ISOIM@Exosome or siBTK@Exosome alone, demonstrating synergistic therapeutic role of ISOIM and si-BTK. Besides, ISOIM/siBTK@Exosome can accelerate T cells activation and prevent macrophage M2 polarization in vitro. Administration of ISOIM/siBTK@Exosome to tumor-bearing mice significantly inhibited tumor growth and prolonged survival. The ISOIM/siBTK@Exosome was biocompatible and biosafe in vivo without damage on the major organs in H&E staining. The prepared ISOIM/siBTK@Exosome may provide novel targeted therapeutic strategy to be applied in the clinical management of patients with DLBCL.</div></div>\",\"PeriodicalId\":18310,\"journal\":{\"name\":\"Materials Today Bio\",\"volume\":\"35 \",\"pages\":\"Article 102267\"},\"PeriodicalIF\":10.2000,\"publicationDate\":\"2025-09-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Materials Today Bio\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2590006425008373\",\"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":"Materials Today Bio","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2590006425008373","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}
Tumor-homing exosomes enable targeted delivery of siRNA and isoimperatorin for overcoming BTK inhibitor resistance in DLBCL
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, but over one-third of patients relapse or develop refractory disease after first-line therapy. Novel therapeutic strategies are required to address persistent unmet clinical needs for DLBCL. This study aimed to develop an exosome-based drug delivery system for the targeted combination therapy of siRNA against Bruton's tyrosine kinase (BTK, an established therapeutic target in B cell lymphomas) and isoimperatorin (ISOIM, an active natural furanocoumarin showing anti-tumor effects) in DLBCL. Tumor exosomes were isolated as the delivery carrier. ISOIM/siBTK@Exosome was prepared by encapsulating ISOIM and si-BTK into exosome using electroporation. Cellular uptake, immune escape, targeted delivery efficiency, anti-lymphoma activity and biosafety of ISOIM/siBTK@Exosome were evaluated in two DLBCL cell lines and in tumor-bearing mice. ISOIM/siBTK@Exosome displayed significant anti-lymphoma activity compared to ISOIM@Exosome or siBTK@Exosome alone, demonstrating synergistic therapeutic role of ISOIM and si-BTK. Besides, ISOIM/siBTK@Exosome can accelerate T cells activation and prevent macrophage M2 polarization in vitro. Administration of ISOIM/siBTK@Exosome to tumor-bearing mice significantly inhibited tumor growth and prolonged survival. The ISOIM/siBTK@Exosome was biocompatible and biosafe in vivo without damage on the major organs in H&E staining. The prepared ISOIM/siBTK@Exosome may provide novel targeted therapeutic strategy to be applied in the clinical management of patients with DLBCL.
期刊介绍:
Materials Today Bio is a multidisciplinary journal that specializes in the intersection between biology and materials science, chemistry, physics, engineering, and medicine. It covers various aspects such as the design and assembly of new structures, their interaction with biological systems, functionalization, bioimaging, therapies, and diagnostics in healthcare. The journal aims to showcase the most significant advancements and discoveries in this field. As part of the Materials Today family, Materials Today Bio provides rigorous peer review, quick decision-making, and high visibility for authors. It is indexed in Scopus, PubMed Central, Emerging Sources, Citation Index (ESCI), and Directory of Open Access Journals (DOAJ).