Cholesterol-conjugated siRNAs can silence gene expression in vivo. Here we synthesize a variety of lipophilic siRNAs and use them to elucidate the requirements for siRNA delivery in vivo. We show that conjugation to bile acids and long-chain fatty acids, in addition to cholesterol, mediates siRNA uptake into cells and gene silencing in vivo. Efficient and selective uptake of these siRNA conjugates depends on interactions with lipoprotein particles, lipoprotein receptors and transmembrane proteins. High-density lipoprotein (HDL) directs siRNA delivery into liver, gut, kidney and steroidogenic organs, whereas low-density lipoprotein (LDL) targets siRNA primarily to the liver. LDL-receptor expression is essential for siRNA delivery by LDL particles, and SR-BI receptor expression is required for uptake of HDL-bound siRNAs. Cellular uptake also requires the mammalian homolog of the Caenorhabditis elegans transmembrane protein Sid1. Our results demonstrate that conjugation to lipophilic molecules enables effective siRNA uptake through a common mechanism that can be exploited to optimize therapeutic siRNA delivery.
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Carbohydr Polym
March 2025
Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore 119276, Singapore; National University of Singapore (Suzhou) Research Institute, Suzhou, Jiangsu 215123, China; National University of Singapore (Chongqing) Research Institute, Yubei, Chongqing 401120, China; NUS Environmental Research Institute (NERI), National University of Singapore, 5A Engineering Drive 1, Singapore 117411, Singapore. Electronic address:
The combination of chemotherapy and gene therapy holds promise in treating cancer. A key strategy is to use small interfering RNAs (siRNAs) to silence programmed death-ligand 1 (PD-L1) expression in cancer cells, disrupting tumor immune evasion and enhancing anticancer treatments, particularly when used in conjunction with chemotherapy drugs such as doxorubicin (Dox). However, effective codelivery of drugs and genes requires carefully designed carriers and complex synthesis procedures.
View Article and Find Full Text PDFAutoimmun Rev
January 2025
The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China. Electronic address:
Autoimmune diseases (ADs) are a group of complex, chronic conditions characterized by disturbance of immune tolerance, with examples including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and psoriasis. These diseases have unclear pathogenesis, and traditional therapeutic approaches remain limited. However, advances in high-throughput histology technology and scientific discoveries have led to the identification of various pathogenic factors contributing to ADs.
View Article and Find Full Text PDFCurr Gene Ther
January 2025
Department of Pharmacology, Faculty of Medicine, The University of Jordan, Queen Rania Al-Abdullah Street, Amman 11942, Jordan.
Introduction: Liposomes are versatile delivery systems for encapsulating small interfering RNAs (siRNAs) because they enhance cellular uptake and gene silencing. This study compares the new liposome formula to commercial lipofectamine in delivering siRNAs targeting hepatic carcinoma genes, focusing on HNF4-α and PFKFB4.
Methods: Flow cytometry and confocal microscopy revealed efficient internalization of PE-Rhod- B labeled lipoplexes in HepG2 cells, while cytotoxicity assays demonstrated significant reductions in cell viability, particularly with siHNF4-α and siPFKFB4.
Drug Deliv Transl Res
January 2025
The Kirby Institute, UNSW Sydney, Sydney, 2052, Australia.
Using the knowledge from decades of research into RNA-based therapies, the COVID-19 pandemic response saw the rapid design, testing and production of the first ever mRNA vaccines approved for human use in the clinic. This breakthrough has been a significant milestone for RNA therapeutics and vaccines, driving an exponential growth of research into the field. The development of novel RNA therapeutics targeting high-threat pathogens, that pose a substantial risk to global health, could transform the future of health delivery.
View Article and Find Full Text PDFACS Omega
January 2025
Institute of Chemical Process Fundamentals Czech Academy of Sciences, Rozvojová 135, Prague 165 02, Czech Republic.
Efficient and safe carriers of genetic material are crucial for advancing gene therapy. Three new series of cationic dendritic nanocarriers based on a carbosilane scaffold, differentiated by peripheral modifications: saccharide (CS-glyco), amine (CS-N), and phosphonium dendrimers (CS-P) were designed for binding, protecting, and releasing polyanionic compounds like therapeutic siRNA. Besides introducing synthetic methodology, this study brings a unique direct interstructural comparison of 16 dendritic nanovector's characteristics, addressing a gap in typical research that focuses on uniform structural types.
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