Directing the Way—Receptor and Chemical Targeting Strategies for Nucleic Acid Delivery

Steffens, Ricarda C.; Wagner, Ernst

doi:10.1007/s11095-022-03385-w

Cited by 22 publications

(23 citation statements)

References 272 publications

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“…The use of different lipid components influences the stability and fusion properties of these lipid nanoparticles. Importantly, by using shielding reagents, protein and non-protein targeting ligands, and different bioresponsive chemical bonds that enable environment-specific dynamics, very specific delivery vectors can be tailored [ 162 ]. Thus, it appears likely that once the genetic material can be successfully delivered to the nucleus, the systems discussed in this review might be delivered both in vitro and in vivo by optimized lipid nanoparticles.…”

Section: Nucleic Acid Deliverymentioning

confidence: 99%

Episomes and Transposases—Utilities to Maintain Transgene Expression from Nonviral Vectors

Kreppel

Hagedorn

2022

Genes

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The efficient delivery and stable transgene expression are critical for applications in gene therapy. While carefully selected and engineered viral vectors allowed for remarkable clinical successes, they still bear significant safety risks. Thus, nonviral vectors are a sound alternative and avoid genotoxicity and adverse immunological reactions. Nonviral vector systems have been extensively studied and refined during the last decades. Emerging knowledge of the epigenetic regulation of replication and spatial chromatin organisation, as well as new technologies, such as Crispr/Cas, were employed to enhance the performance of different nonviral vector systems. Thus, nonviral vectors are in focus and hold some promising perspectives for future applications in gene therapy. This review addresses three prominent nonviral vector systems: the Sleeping Beauty transposase, S/MAR-based episomes, and viral plasmid replicon-based EBV vectors. Exemplarily, we review different utilities, modifications, and new concepts that were pursued to overcome limitations regarding stable transgene expression and mitotic stability. New insights into the nuclear localisation of nonviral vector molecules and the potential consequences thereof are highlighted. Finally, we discuss the remaining limitations and provide an outlook on possible future developments in nonviral vector technology

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Section: Nucleic Acid Deliverymentioning

confidence: 99%

Episomes and Transposases—Utilities to Maintain Transgene Expression from Nonviral Vectors

Kreppel

Hagedorn

2022

Genes

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“…Nucleic acid therapy has shown great potential for the treatment of numerous diseases, such as genetic disorders, cancer, and infection. For example, previous studies have found that the establishment of an siRNA conjugate platform enabled successful subcutaneous delivery of siRNA targeting the Marburg virus nucleoprotein [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Milk-derived exosomes carrying siRNA-KEAP1 promote diabetic wound healing by improving oxidative stress

Xiang

Chen

Jiang

et al. 2023

Drug Deliv. and Transl. Res.

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Diabetic wounds are a serious complication of diabetes mellitus (DM) that can lead to persistent infection, amputation, and even death. Prolonged oxidative stress has been widely recognized as a major instigator in the development of diabetic wounds; therefore, oxidative stress is considered a promising therapeutic target. In the present study, Keap1/Nrf2 signaling was confirmed to be activated in streptozotocin (STZ)-induced diabetic mice and methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). Knockdown of Keap1 by siRNA reversed the increase in Keap1 levels, promoted the nuclear translocation of Nrf2, and increased the expression of HO-1, an antioxidant protein. To explore therapeutic delivery strategies, milk-derived exosomes (mEXOs) were developed as a novel, efficient, and non-toxic siRNA carrier. SiRNA-Keap1 (siKeap1) was loaded into mEXOs by sonication, and the obtained mEXOs-siKeap1 were found to promote HUVEC proliferation and migration while relieving oxidative stress in MGO-treated HUVECs. Meanwhile, in a mouse model of diabetic wounds, injection of mEXOs-siKeap1 significantly accelerated diabetic wound healing with enhanced collagen formation and neovascularization. Taken together, these data support the development of Keap1 knockdown as a potential therapeutic strategy for diabetic wounds and demonstrated the feasibility of mEXOs as a scalable, biocompatible, and cost-effective siRNA delivery system. Graphical Abstract The therapeutic effect of siKeap1-loaded mEXOs on diabetic wound healing was assessed. First, we found that the expression of Keap1 was upregulated in the wounds of diabetic mice and in human umbilical vein endothelial cells (HUVECs) pretreated with methylglyoxal (MGO). Next, we extracted exosomes from raw milk by differential centrifugation and loaded siKeap1 into milk-derived exosomes by sonication. The in vitro application of the synthetic complex (mEXOs-siKeap1) was found to increase the nuclear localization of Nrf2 and the expression of the antioxidant protein HO-1, thus reversing oxidative stress. Furthermore, in vivo mEXOs-siKeap1 administration significantly accelerated the healing rate of diabetic wounds (Scheme 1). Scheme 1 Schematic diagram. A Synthesis of mEXOs-siKeap1 complex. B Mechanism of mEXOs-siKeap1 in vitro. C The treatment effect of mEXOs-siKeap1 on an in vivo mouse model of diabetic wounds Supplementary Information The online version contains supplementary material available at 10.1007/s13346-023-01306-x.

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“…Another challenge limiting the wide application of tNAs is the inability of tNAs to cross the plasma membrane barrier of cells. This is why different carriers have been developed to improve the intracellular/intratissue accumulation of tNAs [ 26 , 27 , 28 , 29 ], including those proving for targeted delivery. Despite the considerable progress made in this field, major challenges remain to be overcome: some carriers cause immunological problems or are unable to overcome the biological barriers on their way to the target; some of them are rapidly excreted by the kidney or are accumulated intensively and metabolized by the liver.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles for Therapeutic Nucleic Acid Delivery: Loading Strategies and Challenges

Oshchepkova

Zenkova

Vlassov

2023

IJMS

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Extracellular vesicles (EVs) are membrane vesicles released into the extracellular milieu by cells of various origins. They contain different biological cargoes, protecting them from degradation by environmental factors. There is an opinion that EVs have a number of advantages over synthetic carriers, creating new opportunities for drug delivery. In this review, we discuss the ability of EVs to function as carriers for therapeutic nucleic acids (tNAs), challenges associated with the use of such carriers in vivo, and various strategies for tNA loading into EVs.

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Directing the Way—Receptor and Chemical Targeting Strategies for Nucleic Acid Delivery

Cited by 22 publications

References 272 publications

Episomes and Transposases—Utilities to Maintain Transgene Expression from Nonviral Vectors

Episomes and Transposases—Utilities to Maintain Transgene Expression from Nonviral Vectors

Milk-derived exosomes carrying siRNA-KEAP1 promote diabetic wound healing by improving oxidative stress

Extracellular Vesicles for Therapeutic Nucleic Acid Delivery: Loading Strategies and Challenges

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