bims-novged Biomed News
on Non-viral vectors for gene delivery
Issue of 2023–12–17
nine papers selected by
the Merkel lab, Ludwig-Maximilians University
  1. Delivery of nucleic acids using nanomaterials.
  2. On the interactions between RNA and titrateable lipid layers: implications for RNA delivery with lipid nanoparticles.
  3. mRNA extraction from lipid nanoparticles.
  4. Engineering carrier nanoparticles with biomimetic moieties for improved intracellular targeted delivery of mRNA therapeutics and vaccines.
  5. Straight to the point: targeted mRNA-delivery to immune cells for improved vaccine design.
  6. Nucleic acid degradation as barrier to gene delivery: a guide to understand and overcome nuclease activity.
  7. Considerations on the design of lipid-based mRNA vaccines against cancer.
  8. Lipid-Based Nanoparticles for Drug/Gene Delivery: An Overview of the Production Techniques and Difficulties Encountered in Their Industrial Development.
  9. Effects of PEG antibodies on in vivo performance of LNP-mRNA vaccines.
  1. Mol Biomed. 2023 Dec 14. 4(1): 48
    Delivery of nucleic acids using nanomaterials.
    Yuyang Qin, Liyuan Ou, Lili Zha, Yue Zeng, Ling Li.
      The increasing number of approved nucleic acid therapeutics demonstrates the potential for the prevention and treatment of a broad spectrum of diseases. This trend underscores the significant impact and promise of nucleic acid-based treatments in the field of medicine. Nevertheless, employing nucleic acids as therapeutics is challenging due to their susceptibility to degradation by nucleases and their unfavorable physicochemical characteristics that hinder delivery into cells. Appropriate vectors play a pivotal role in improving nucleic acid stability and delivering nucleic acids into specific cells. The maturation of delivery systems has led to breakthroughs in the development of therapeutics based on nucleic acids such as DNA, siRNA, and mRNA. Non-viral vectors have gained prominence among the myriad of nanomaterials due to low immunogenicity, ease of manufacturing, and simplicity of cost-effective, large-scale production. Here, we provide an overview of the recent advancements in nanomaterials for nucleic acid delivery. Specifically, we give a detailed introduction to the characteristics of polymers, lipids, and polymer-lipid hybrids, and provide comprehensive descriptions of their applications in nucleic acid delivery. Also, biological barriers, administration routes, and strategies for organ-selective delivery of nucleic acids are discussed. In summary, this review offers insights into the rational design of next-generation delivery vectors for nucleic acid delivery.
    Keywords:  Nanomaterials; Non-viral vectors; Nucleic acids; Organ-selective delivery
    DOI:  https://doi.org/10.1186/s43556-023-00160-0
  2. Nanoscale. 2023 Dec 13.
    On the interactions between RNA and titrateable lipid layers: implications for RNA delivery with lipid nanoparticles.
    Jennifer Gilbert, Inna Ermilova, Marco Fornasier, Maximilian Skoda, Giovanna Fragneto, Jan Swenson, Tommy Nylander.
      Characterising the interaction between cationic ionisable lipids (CIL) and nucleic acids (NAs) is key to understanding the process of RNA lipid nanoparticle (LNP) formation and release of NAs from LNPs. Here, we have used different surface techniques to reveal the effect of pH and NA type on the interaction with a model system of DOPC and the CIL DLin-MC3-DMA (MC3). At only 5% MC3, differences in the structure and dynamics of the lipid layer were observed. Both pH and %MC3 were shown to affect the absorption behaviour of erythropoietin mRNA, polyadenylic acid (polyA) and polyuridylic acid (polyU). The adsorbed amount of all studied NAs was found to increase with decreasing pH and increasing %MC3 but with different effects on the lipid layer, which could be linked to the NA secondary structure. For polyA at pH 6, adsorption to the surface of the layer was observed, whereas for other conditions and NAs, penetration of the NA into the layer resulted in the formation of a multilayer structure. By comparison to simulations excluding the secondary structure, differences in adsorption behaviours between polyA and polyU could be observed, indicating that the NA's secondary structure also affected the MC3-NA interactions.
    DOI:  https://doi.org/10.1039/d3nr03308b
  3. J Chromatogr A. 2023 Dec 01. pii: S0021-9673(23)00770-7. [Epub ahead of print]1714 464545
    mRNA extraction from lipid nanoparticles.
    Camille Malburet, Aurelien Carboni, Stephanie Guinamand, Hemantkumar Naik, Stephanie Fertier-Prizzon.
      Messenger RiboNucleic Acid (mRNA) vaccines have recently shown considerable promises for both prophylactic and therapeutic vaccines. These vaccines do not carry an antigen but the information for producing it using the cell machinery, turning the human body into an antigen factory. However, mRNA is an unstable molecule, susceptible to physical, chemical and enzymatic degradation by exo- and endonucleases. If the mRNA is degraded, it can no longer be translated correctly into the antigen of interest and the vaccine lose its efficacy. To protect from nucleases degradation and allow it to get into the cells, mRNA can be encapsulated in lipid nanoparticles (LNPs). As part of the manufacturing process, the quality of the mRNAs should be controlled before the encapsulation (at the drug substance stage) as well as after formulation on the final vaccine product (at the drug product stage). Therefore, it is necessary to be able to extract the mRNA from the LNPs, that is to deformulate the final vaccine product. In this work, different deformulation methods have been compared: spin column extraction, magnetic particle extraction, organic extraction, and direct disruption. Advantages and disadvantages of each of these methods are highlighted.
    Keywords:  Deformulation; Extraction; Integrity; Lipid nanoparticle; mRNA
    DOI:  https://doi.org/10.1016/j.chroma.2023.464545
  4. J Pharm Pharmacol. 2023 Dec 13. pii: rgad089. [Epub ahead of print]
    Engineering carrier nanoparticles with biomimetic moieties for improved intracellular targeted delivery of mRNA therapeutics and vaccines.
    Matteo Puccetti, Marilena Pariano, Aurelie Schoubben, Maurizio Ricci, Stefano Giovagnoli.
      Biological membrane-engineered lipid nanoparticles (LNP) have shown enormous potential as vehicles for drug delivery due to their outstanding biomimetic properties. To make these nanoparticles more adaptable to complex biological systems, several methods and cellular sources have been adopted to introduce biomembrane-derived moieties onto LNP and provide the latter with more functions while preserving their intrinsic nature. In this review, we focus on LNP decoration with specific regard to mRNA therapeutics and vaccines. The bio-engineering approach exploits a variety of biomembranes for functionalization, such as those derived from red blood cells, white blood cells, cancer cells, platelets, exosomes, and others. Biomembrane engineering could greatly enhance efficiency in targeted drug delivery, treatment, and diagnosis of cancer, inflammation, immunological diseases, and a variety of pathologic conditions. These membrane-modification techniques are expected to advance biomembrane-derived LNP into wider applications in the future.
    Keywords:  drug delivery system; mRNA therapeutics; nanoparticles; target therapy; theranostics
    DOI:  https://doi.org/10.1093/jpp/rgad089
  5. Front Immunol. 2023 ;14 1294929
    Straight to the point: targeted mRNA-delivery to immune cells for improved vaccine design.
    Bruna Clemente, Maxime Denis, Camila Pedroso Silveira, Francesca Schiavetti, Michela Brazzoli, Daniela Stranges.
      With the deepening of our understanding of adaptive immunity at the cellular and molecular level, targeting antigens directly to immune cells has proven to be a successful strategy to develop innovative and potent vaccines. Indeed, it offers the potential to increase vaccine potency and/or modulate immune response quality while reducing off-target effects. With mRNA-vaccines establishing themselves as a versatile technology for future applications, in the last years several approaches have been explored to target nanoparticles-enabled mRNA-delivery systems to immune cells, with a focus on dendritic cells. Dendritic cells (DCs) are the most potent antigen presenting cells and key mediators of B- and T-cell immunity, and therefore considered as an ideal target for cell-specific antigen delivery. Indeed, improved potency of DC-targeted vaccines has been proved in vitro and in vivo. This review discusses the potential specific targets for immune system-directed mRNA delivery, as well as the different targeting ligand classes and delivery systems used for this purpose.
    Keywords:  C-type lectins; dendritic cells; lipid nanoparticles; mRNA vaccine; targeted delivery
    DOI:  https://doi.org/10.3389/fimmu.2023.1294929
  6. Chem Soc Rev. 2023 Dec 11.
    Nucleic acid degradation as barrier to gene delivery: a guide to understand and overcome nuclease activity.
    Heyang Zhang, Jo Vandesompele, Kevin Braeckmans, Stefaan C De Smedt, Katrien Remaut.
      Gene therapy is on its way to revolutionize the treatment of both inherited and acquired diseases, by transferring nucleic acids to correct a disease-causing gene in the target cells of patients. In the fight against infectious diseases, mRNA-based therapeutics have proven to be a viable strategy in the recent Covid-19 pandemic. Although a growing number of gene therapies have been approved, the success rate is limited when compared to the large number of preclinical and clinical trials that have been/are being performed. In this review, we highlight some of the hurdles which gene therapies encounter after administration into the human body, with a focus on nucleic acid degradation by nucleases that are extremely abundant in mammalian organs, biological fluids as well as in subcellular compartments. We overview the available strategies to reduce the biodegradation of gene therapeutics after administration, including chemical modifications of the nucleic acids, encapsulation into vectors and co-administration with nuclease inhibitors and discuss which strategies are applied for clinically approved nucleic acid therapeutics. In the final part, we discuss the currently available methods and techniques to qualify and quantify the integrity of nucleic acids, with their own strengths and limitations.
    DOI:  https://doi.org/10.1039/d3cs00194f
  7. J Mol Biol. 2023 Dec 06. pii: S0022-2836(23)00496-5. [Epub ahead of print] 168385
    Considerations on the design of lipid-based mRNA vaccines against cancer.
    Sofie Meulewaeter, Yao Zhang, Abishek Wadhwa, Kevin Fox, Ine Lentacker, Kenneth W Harder, Pieter R Cullis, Stefaan C De Smedt, Miffy H Y Cheng, Rein Verbeke.
      Throughout the last decades, mRNA vaccines have been developed as a cancer immunotherapeutic and the technology recently gained momentum during the COVID-19 pandemic. Recent promising results obtained from clinical trials investigating lipid-based mRNA vaccines in cancer therapy further highlighted the potential of this therapy. Interestingly, while the technologies being used in authorized mRNA vaccines for the prevention of COVID-19 are relatively similar, mRNA vaccines in clinical development for cancer vaccination show marked differences in mRNA modification, lipid carrier, and administration route. In this review, we describe findings on how these factors can impact the potency of mRNA vaccines in cancer therapy and provide insights into the complex interplay between them. We discuss how lipid carrier composition can affect passive targeting to immune cells to improve the efficacy and safety of mRNA vaccines. Finally, we summarize strategies that are established or still being explored to improve the efficacy of mRNA cancer vaccines and include next-generation vaccines that are on the horizon in clinical development.
    Keywords:  ADJUVANT; CANCER VACCINES; INNATE IMMUNITY; LIPID NANOPARTICLES; LIPOPLEXES; MRNA VACCINE; ROUTE OF ADMINISTRATION
    DOI:  https://doi.org/10.1016/j.jmb.2023.168385
  8. ACS Mater Au. 2023 Nov 08. 3(6): 600-619
    Lipid-Based Nanoparticles for Drug/Gene Delivery: An Overview of the Production Techniques and Difficulties Encountered in Their Industrial Development.
    Meenu Mehta, Thuy Anh Bui, Xinpu Yang, Yagiz Aksoy, Ewa M Goldys, Wei Deng.
      Over the past decade, the therapeutic potential of nanomaterials as novel drug delivery systems complementing conventional pharmacology has been widely acknowledged. Among these nanomaterials, lipid-based nanoparticles (LNPs) have shown remarkable pharmacological performance and promising therapeutic outcomes, thus gaining substantial interest in preclinical and clinical research. In this review, we introduce the main types of LNPs used in drug formulations such as liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and lipid polymer hybrid nanoparticles, focusing on their main physicochemical properties and therapeutic potential. We discuss computational studies and modeling techniques to enhance the understanding of how LNPs interact with therapeutic cargo and to predict the potential effectiveness of such interactions in therapeutic applications. We also analyze the benefits and drawbacks of various LNP production techniques such as nanoprecipitation, emulsification, evaporation, thin film hydration, microfluidic-based methods, and an impingement jet mixer. Additionally, we discuss the major challenges associated with industrial development, including stability and sterilization, storage, regulatory compliance, reproducibility, and quality control. Overcoming these challenges and facilitating regulatory compliance represent the key steps toward LNP's successful commercialization and translation into clinical settings.
    DOI:  https://doi.org/10.1021/acsmaterialsau.3c00032
  9. Int J Pharm. 2023 Dec 09. pii: S0378-5173(23)01117-1. [Epub ahead of print] 123695
    Effects of PEG antibodies on in vivo performance of LNP-mRNA vaccines.
    Min Yang, Zengyu Zhang, Pengpeng Jin, Kuan Jiang, Yifei Xu, Feng Pan, Kaisong Tian, Zhou Yuan, Xiaohua Eric Liu, Jiaru Fu, Bin Wang, Huafang Yan, Changyou Zhan, Zui Zhang.
      Polyethylene glycol (PEG) plays important roles in stabilizing and lengthening circulation time of lipid nanoparticle (LNP) vaccines. Nowadays various levels of PEG antibodies have been detected in human blood, but the impact and mechanism of PEG antibodies on the in vivo performance of LNP vaccines has not been clarified thoroughly. By illustrating the distribution characteristics of PEG antibodies in human, the present study focused on the influence of PEG antibodies on the safety and efficacy of LNP-mRNA vaccine against COVID-19 in animal models. It was found that PEG antibodies led to shortened blood circulation duration, elevated accumulation and mRNA expression in liver and spleen, enhanced expression in macrophage and dendritic cells, while without affecting the production of anti-Spike protein antibodies of COVID-19 LNP vaccine. Noteworthily, PEG antibodies binding on the LNP vaccine increased probability of complement activation in animal as well as in human serum and led to lethal side effect in large dosage via intravenous injection of mice. Our data suggested that PEG antibodies in human was a risky factor of LNP-based vaccines for biosafety concerns but not efficacy.
    Keywords:  COVID-19 vaccine; PEG antibody; complement activation; hypersensitivity; lipid nanoparticle
    DOI:  https://doi.org/10.1016/j.ijpharm.2023.123695
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