A proton/macromolecule-sensing approach distinguishes changes in biological membrane permeability during polymer/lipid-based nucleic acid delivery

2021 ◽  
Author(s):  
Eger Boonstra ◽  
Hiroaki Hatano ◽  
Yuji Miyahara ◽  
Satoshi Uchida ◽  
Tatsuro Goda ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Membrane Permeability ◽  
Biological Membrane ◽  
Endosomal Escape ◽  
Nucleic Acid Delivery ◽  
Underlying Mechanisms

Endosomal escape is crucial for the delivery of nucleic acids. However, the understanding of the underlying mechanisms is still deficient. In this work, we explored the effects of lipid- and...

scholarly journals Viral Mimicry as a Design Template for Nucleic Acid Nanocarriers

2021 ◽  
Vol 9 ◽  
Author(s):  
Ina F. de la Fuente ◽  
Shraddha S. Sawant ◽  
Mark Q. Tolentino ◽  
Patrick M. Corrigan ◽  
Jessica L. Rouge
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Molecular Mechanisms ◽  
Transfection Efficiency ◽  
Delivery Systems ◽  
Endosomal Escape ◽  
Nucleic Acid Delivery ◽  
Metastable Structure ◽  
Oligonucleotide Delivery ◽  
Genome Protection

Therapeutic nucleic acids hold immense potential in combating undruggable, gene-based diseases owing to their high programmability and relative ease of synthesis. While the delivery of this class of therapeutics has successfully entered the clinical setting, extrahepatic targeting, endosomal escape efficiency, and subcellular localization. On the other hand, viruses serve as natural carriers of nucleic acids and have acquired a plethora of structures and mechanisms that confer remarkable transfection efficiency. Thus, understanding the structure and mechanism of viruses can guide the design of synthetic nucleic acid vectors. This review revisits relevant structural and mechanistic features of viruses as design considerations for efficient nucleic acid delivery systems. This article explores how viral ligand display and a metastable structure are central to the molecular mechanisms of attachment, entry, and viral genome release. For comparison, accounted for are details on the design and intracellular fate of existing nucleic acid carriers and nanostructures that share similar and essential features to viruses. The review, thus, highlights unifying themes of viruses and nucleic acid delivery systems such as genome protection, target specificity, and controlled release. Sophisticated viral mechanisms that are yet to be exploited in oligonucleotide delivery are also identified as they could further the development of next-generation nonviral nucleic acid vectors.

scholarly journals Peptide-Assisted Nucleic Acid Delivery Systems on the Rise

2021 ◽  
Vol 22 (16) ◽  
pp. 9092
Author(s):  
Shabnam Tarvirdipour ◽  
Michal Skowicki ◽  
Cora-Ann Schoenenberger ◽  
Cornelia G. Palivan
Keyword(s):  
Nucleic Acid ◽  
Side Effects ◽  
Nucleic Acids ◽  
Delivery Systems ◽  
Inorganic Nanoparticles ◽  
Water Soluble ◽  
Nucleic Acid Delivery ◽  
Subcellular Organelles ◽  
Cell Internalization ◽  
Site Of Action

Concerns associated with nanocarriers’ therapeutic efficacy and side effects have led to the development of strategies to advance them into targeted and responsive delivery systems. Owing to their bioactivity and biocompatibility, peptides play a key role in these strategies and, thus, have been extensively studied in nanomedicine. Peptide-based nanocarriers, in particular, have burgeoned with advances in purely peptidic structures and in combinations of peptides, both native and modified, with polymers, lipids, and inorganic nanoparticles. In this review, we summarize advances on peptides promoting gene delivery systems. The efficacy of nucleic acid therapies largely depends on cell internalization and the delivery to subcellular organelles. Hence, the review focuses on nanocarriers where peptides are pivotal in ferrying nucleic acids to their site of action, with a special emphasis on peptides that assist anionic, water-soluble nucleic acids in crossing the membrane barriers they encounter on their way to efficient function. In a second part, we address how peptides advance nanoassembly delivery tools, such that they navigate delivery barriers and release their nucleic acid cargo at specific sites in a controlled fashion.

Nucleic Acid Delivery System by the Combination of Lipid bubbles and Ultrasound

2018 ◽  
Vol 24 (23) ◽  
pp. 2673-2677 ◽  
Author(s):  
Yoko Endo-Takahashi ◽  
Kazuo Maruyama ◽  
Yoichi Negishi
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Delivery System ◽  
Target Genes ◽  
Delivery Systems ◽  
Target Site ◽  
Therapeutic Effects ◽  
Nucleic Acid Delivery ◽  
Clinical Implementation ◽  
Systemic Delivery

Background: RNA interference (RNAi)-based therapy has gained attention because of its potent genesilencing effect and high specificity. However, the efficient delivery of nucleic acids to the target site is a major challenge to the clinical implementation. Recently, ultrasound-mediated gene delivery systems have been developed and attracted interest due to its safety and site-specificity. By the combination with contrast agents, called microbubbles, not only the delivery effects but also the imaging effects are significantly enhanced. We developed lipid bubbles (LBs) entrapping an ultrasound contrast gas to enhance the efficacy of ultrasound-mediated delivery and imaging. In this review, we summarize ultrasound-mediated nucleic acid delivery systems and discuss the possibility of combining LBs and ultrasound for RNAi-based therapies. Methods: We prepared polyethylene glycol-modified liposomes and entrapped an echo-contrast gas within the liposomes. Small interfering RNA (siRNA) were transfected into cells and muscles using LBs and ultrasound. Moreover, we also developed nucleic acid-loaded LBs using cholesterol-conjugated siRNA or positively-charged lipid for an efficient systemic delivery of siRNA and microRNA. The usability of LBs for RNA delivery system was evaluated by the silencing effects of target genes and the therapeutic effects on ischemia hind limb. Results: A combination of LBs and therapeutic ultrasound was able to enhance the gene silencing effects by siRNA. Nucleic acid-loaded LBs were able to efficiently deliver siRNA or microRNA by systemic administration. A combination of LBs and diagnostic ultrasound also enhanced the imaging efficiency. Using a hindlimb ischemia mouse model, microRNA-loaded LBs could lead to increased angiogenic factors and improved blood flow. Conclusion: Ultrasound technology is widely used in clinical settings not only for diagnosis but also for therapy. Ultrasonic devices are being actively developed. Computer-controlled ultrasound systems can provide precise exposure to the target site. The combination of precise ultrasound exposure and LBs might be useful for target site-specific nucleic acids delivery, and holds potential to be developed into a beneficial therapeutic and diagnostic system for various diseases.

scholarly journals Multifunctional Immunoadjuvants for Use in Minimalist Nucleic Acid Vaccines

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 644
Author(s):  
Saed Abbasi ◽  
Satoshi Uchida
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Nucleic Acids ◽  
Innate Immune ◽  
Great Promise ◽  
Nucleic Acid Delivery ◽  
Subunit Vaccines ◽  
Adaptive Immune ◽  
Nucleic Acid Vaccines ◽  
And Control

Subunit vaccines based on antigen-encoding nucleic acids have shown great promise for antigen-specific immunization against cancer and infectious diseases. Vaccines require immunostimulatory adjuvants to activate the innate immune system and trigger specific adaptive immune responses. However, the incorporation of immunoadjuvants into nonviral nucleic acid delivery systems often results in fairly complex structures that are difficult to mass-produce and characterize. In recent years, minimalist approaches have emerged to reduce the number of components used in vaccines. In these approaches, delivery materials, such as lipids and polymers, and/or pDNA/mRNA are designed to simultaneously possess several functionalities of immunostimulatory adjuvants. Such multifunctional immunoadjuvants encode antigens, encapsulate nucleic acids, and control their pharmacokinetic or cellular fate. Herein, we review a diverse class of multifunctional immunoadjuvants in nucleic acid subunit vaccines and provide a detailed description of their mechanisms of adjuvanticity and induction of specific immune responses.

scholarly journals Synthetic Approaches for Nucleic Acid Delivery: Choosing the Right Carriers

Life ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 59 ◽  
Author(s):  
Rong Ni ◽  
Ruilu Feng ◽  
Ying Chau
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Genetic Disorders ◽  
Chemical Properties ◽  
Nucleic Acid Delivery ◽  
Translation Inhibition ◽  
Different Types ◽  
Function Correlation ◽  
The Right ◽  
Synthetic Approaches

The discovery of the genetic roots of various human diseases has motivated the exploration of different exogenous nucleic acids as therapeutic agents to treat these genetic disorders (inherited or acquired). However, the physicochemical properties of nucleic acids render them liable to degradation and also restrict their cellular entrance and gene translation/inhibition at the correct cellular location. Therefore, gene condensation/protection and guided intracellular trafficking are necessary for exogenous nucleic acids to function inside cells. Diversified cationic formulation materials, including natural and synthetic lipids, polymers, and proteins/peptides, have been developed to facilitate the intracellular transportation of exogenous nucleic acids. The chemical properties of different formulation materials determine their special features for nucleic acid delivery, so understanding the property–function correlation of the formulation materials will inspire the development of next-generation gene delivery carriers. Therefore, in this review, we focus on the chemical properties of different types of formulation materials and discuss how these formulation materials function as protectors and cellular pathfinders for nucleic acids, bringing them to their destination by overcoming different cellular barriers.

scholarly journals A library of aminoglycoside-derived lipopolymer nanoparticles for delivery of small molecules and nucleic acids

2020 ◽  
Vol 8 (37) ◽  
pp. 8558-8572
Author(s):  
Sudhakar Godeshala ◽  
Bhavani Miryala ◽  
Subhadeep Dutta ◽  
Matthew D. Christensen ◽  
Purbasha Nandi ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Small Molecules ◽  
Small Molecule ◽  
Nucleic Acid Delivery ◽  
Small Molecule Drug

A library of lipopolymer nanoparticles for nucleic acid, small-molecule drug, and simultaneous drug and nucleic acid delivery.

scholarly journals The Multifaceted Histidine-Based Carriers for Nucleic Acid Delivery: Advances and Challenges

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 774
Author(s):  
Jiaxi He ◽  
Songhui Xu ◽  
A. James Mixson
Keyword(s):  
Nucleic Acid ◽  
Hydrogen Bonds ◽  
Mesoporous Silica ◽  
Nucleic Acids ◽  
Imidazole Ring ◽  
Great Promise ◽  
Nucleic Acid Delivery ◽  
Acidic Environments ◽  
The Stability ◽  
Intracellular Targets

Histidines incorporated into carriers of nucleic acids may enhance the extracellular stability of the nanoparticle, yet aid in the intracellular disruption of the nanoparticle, enabling the release of the nucleic acid. Moreover, protonation of histidines in the endosomes may result in endosomal swelling with subsequent lysis. These properties of histidine are based on its five-member imidazole ring in which the two nitrogen atoms may form hydrogen bonds or act as a base in acidic environments. A wide variety of carriers have integrated histidines or histidine-rich domains, which include peptides, polyethylenimine, polysaccharides, platform delivery systems, viral phages, mesoporous silica particles, and liposomes. Histidine-rich carriers have played key roles in our understanding of the stability of nanocarriers and the escape of the nucleic acids from endosomes. These carriers show great promise and offer marked potential in delivering plasmids, siRNA, and mRNA to their intracellular targets.

scholarly journals Solid-phase supported design of carriers for therapeutic nucleic acid delivery

2017 ◽  
Vol 37 (5) ◽  
Author(s):  
Ana Krhac Levacic ◽  
Stephan Morys ◽  
Ernst Wagner
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Solid Phase ◽  
Nucleic Acid Delivery ◽  
Chemical Production ◽  
Nucleic Acid Therapeutics ◽  
Gene Therapies ◽  
Current Review ◽  
Medical Translation ◽  
Site Of Action

Nucleic acid molecules are important therapeutic agents in the field of antisense oligonucleotide, RNA interference, and gene therapies. Since nucleic acids are not able to cross cell membranes and enter efficiently into cells on their own, the development of efficient, safe, and precise delivery systems is the crucial challenge for development of nucleic acid therapeutics. For the delivery of nucleic acids to their intracellular site of action, either the cytosol or the nucleus, several extracellular and intracellular barriers have to be overcome. Multifunctional carriers may handle the different special requirements of each barrier. The complexity of such macromolecules however poses a new hurdle in medical translation, which is the chemical production in reproducible and well-defined form. Solid-phase assisted synthesis (SPS) presents a solution for this challenge. The current review provides an overview on the design and SPS of precise sequence-defined synthetic carriers for nucleic acid cargos.

Polymers and hydrogels for local nucleic acid delivery

2018 ◽  
Vol 6 (36) ◽  
pp. 5651-5670 ◽  
Author(s):  
Lies A. L. Fliervoet ◽  
Johan F. J. Engbersen ◽  
Raymond M. Schiffelers ◽  
Wim E. Hennink ◽  
Tina Vermonden
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Rational Design ◽  
Local Delivery ◽  
Nucleic Acid Delivery

This review focusses on the rational design of materials (from polymers to hydrogel materials) to achieve successful local delivery of therapeutic nucleic acids.

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