{"title":"Engineered Extracellular Vesicles for Tumor-Targeted Delivery of Therapeutic siRNA for Lung Cancer Therapy.","authors":"Rahmat Asfiya, Anjugam Paramanantham, Ragavi Premnath, Grace McCully, Fatimah Yousuf, Gregory Goetz, Akhil Srivastava","doi":"10.1021/acsbiomaterials.5c00434","DOIUrl":null,"url":null,"abstract":"<p><p>RNAi-based technologies offer the potential to treat cancer effectively, but safe and efficient RNA administration remains a barrier to their clinical adoption. In this study, we developed extracellular vesicles (EVs) and a gold nanoparticle (GNP)-based hybrid system for the targeted delivery of therapeutic siRNA. We used siRNA to silence the B7-H4 encoding gene (a B7 family immune checkpoint protein, gene <i>VTCN1</i>). The knockdown of B7-H4 inhibits proliferation, invasion, and migration in cancer cell lines and increases apoptosis levels. The standardized nanocomplex of GNPs and B7-H4 siRNA (GNPs-siR<sub>B</sub>) was hybridized with EVs by a heat shock technique in the presence of CaCl<sub>2</sub> to form the EV-siR<sub>B</sub> hybrid system. Furthermore, the system's ability to selectively deliver siRNA was examined in two Non-Small Cell Lung Cancer (NSCLC) cell lines, viz., H1299 and A549, as well as in a normal lung fibroblast cell line (MRC9). We found that the standard dose of EV-siR<sub>B</sub> effectively knocked down B7-H4 in cancer cells H1299 and A549 and their spheroids. However, it was less effective in normal lung cells (MRC9). Finally, we demonstrated the antitumor therapeutic effect of the EV-siR<sub>B</sub> complex in NSCLC xenograft models. The results from this study highlight the effectiveness of the hybrid EV-siR<sub>B</sub> system in delivering therapeutic siRNA to tumor cells and open an avenue to explore the efficacy of the system in patient-derived NSCLC and other solid tumor models.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":" ","pages":"4206-4218"},"PeriodicalIF":5.5000,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Biomaterials Science & Engineering","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1021/acsbiomaterials.5c00434","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/10 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"MATERIALS SCIENCE, BIOMATERIALS","Score":null,"Total":0}
引用次数: 0
Abstract
RNAi-based technologies offer the potential to treat cancer effectively, but safe and efficient RNA administration remains a barrier to their clinical adoption. In this study, we developed extracellular vesicles (EVs) and a gold nanoparticle (GNP)-based hybrid system for the targeted delivery of therapeutic siRNA. We used siRNA to silence the B7-H4 encoding gene (a B7 family immune checkpoint protein, gene VTCN1). The knockdown of B7-H4 inhibits proliferation, invasion, and migration in cancer cell lines and increases apoptosis levels. The standardized nanocomplex of GNPs and B7-H4 siRNA (GNPs-siRB) was hybridized with EVs by a heat shock technique in the presence of CaCl2 to form the EV-siRB hybrid system. Furthermore, the system's ability to selectively deliver siRNA was examined in two Non-Small Cell Lung Cancer (NSCLC) cell lines, viz., H1299 and A549, as well as in a normal lung fibroblast cell line (MRC9). We found that the standard dose of EV-siRB effectively knocked down B7-H4 in cancer cells H1299 and A549 and their spheroids. However, it was less effective in normal lung cells (MRC9). Finally, we demonstrated the antitumor therapeutic effect of the EV-siRB complex in NSCLC xenograft models. The results from this study highlight the effectiveness of the hybrid EV-siRB system in delivering therapeutic siRNA to tumor cells and open an avenue to explore the efficacy of the system in patient-derived NSCLC and other solid tumor models.
期刊介绍：
ACS Biomaterials Science & Engineering is the leading journal in the field of biomaterials, serving as an international forum for publishing cutting-edge research and innovative ideas on a broad range of topics:
Applications and Health – implantable tissues and devices, prosthesis, health risks, toxicology
Bio-interactions and Bio-compatibility – material-biology interactions, chemical/morphological/structural communication, mechanobiology, signaling and biological responses, immuno-engineering, calcification, coatings, corrosion and degradation of biomaterials and devices, biophysical regulation of cell functions
Characterization, Synthesis, and Modification – new biomaterials, bioinspired and biomimetic approaches to biomaterials, exploiting structural hierarchy and architectural control, combinatorial strategies for biomaterials discovery, genetic biomaterials design, synthetic biology, new composite systems, bionics, polymer synthesis
Controlled Release and Delivery Systems – biomaterial-based drug and gene delivery, bio-responsive delivery of regulatory molecules, pharmaceutical engineering
Healthcare Advances – clinical translation, regulatory issues, patient safety, emerging trends
Imaging and Diagnostics – imaging agents and probes, theranostics, biosensors, monitoring
Manufacturing and Technology – 3D printing, inks, organ-on-a-chip, bioreactor/perfusion systems, microdevices, BioMEMS, optics and electronics interfaces with biomaterials, systems integration
Modeling and Informatics Tools – scaling methods to guide biomaterial design, predictive algorithms for structure-function, biomechanics, integrating bioinformatics with biomaterials discovery, metabolomics in the context of biomaterials
Tissue Engineering and Regenerative Medicine – basic and applied studies, cell therapies, scaffolds, vascularization, bioartificial organs, transplantation and functionality, cellular agriculture
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