bims-novged 2024-01-21 papers

bims-novged

Biomed News

on Non-viral vectors for gene delivery

Issue of 2024‒01‒21
ten papers selected by
the Merkel lab, Ludwig-Maximilians University

The Immunostimulatory Nature of mRNA Lipid Nanoparticles.
Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach.
Lipid- and Polymer-Based Nanocarrier Platforms for Cancer Vaccine Delivery.
Recent advances in molecular targeted therapy of lung cancer: Possible application in translation medicine.
Induced Self-Assembly of Vitamin E-Spermine/Sirna Nanocomplexes via Spermine/Helix Groove-Specific Interaction for Efficient Sirna Delivery and Antitumor Therapy.
Recent Progress in the Endosomal Escape Mechanism and Chemical Structures of Polycations for Nucleic Acid Delivery.
Tailoring Gene Transfer Efficacy through the Arrangement of Cationic and Anionic Blocks in Triblock Copolymer Micelles.
Advancing cancer treatment: in vivo delivery of therapeutic small noncoding RNAs.
Lymph node macrophages drive innate immune responses to enhance the anti-tumor efficacy of mRNA vaccines.
Navigating the challenges of lipid nanoparticle formulation: the role of unpegylated lipid surfactants in enhancing drug loading and stability.

Adv Drug Deliv Rev. 2024 Jan 11. pii: S0169-409X(23)00490-8. [Epub ahead of print] 115175

The Immunostimulatory Nature of mRNA Lipid Nanoparticles.

Preeti Sharma, Daniek Hoorn, Anjaiah Aitha, Dor Breier, Dan Peer.

  mRNA-Lipid nanoparticles (LNPs) are at the forefront of global medical research. With the development of mRNA-LNP vaccines to combat the COVID-19 pandemic, the clinical potential of this platform was unleashed. Upon administering 16 billion doses that protected billions of people, it became clear that a fraction of them witnessed mild and in some cases even severe adverse effects. Therefore, it is paramount to define the safety along with the therapeutic efficacy of the mRNA-LNP platform for the successful translation of new genetic medicines based on this technology. While mRNA was the effector molecule of this platform, the ionizable lipid component of the LNPs played an indispensable role in its success. However, both of these components possess the ability to induce undesired immunostimulation, which is an area that needs to be addressed systematically. The immune cell agitation caused by this platform is a two-edged sword as it may prove beneficial for vaccination but detrimental to other applications. Therefore, a key challenge in advancing the mRNA-LNP drug delivery platform from bench to bedside is understanding the immunostimulatory behavior of these components. Herein, we provide a detailed overview of the structural modifications and immunogenicity of synthetic mRNA. We discuss the effect of ionizable lipid structure on LNP functionality and offer a mechanistic overview of the ability of LNPs to elicit an immune response. Finally, we shed some light on the current status of this technology in clinical trials and discuss a few challenges to be addressed to advance the field.

Keywords:  adverse events; immunogenicity; ionizable lipids; mRNA vaccines; structure-activity relationship

DOI:  https://doi.org/10.1016/j.addr.2023.115175
Bioact Mater. 2024 Apr;34 125-137

Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach.

Rachel E Young, Katherine M Nelson, Samuel I Hofbauer, Tara Vijayakumar, Mohamad-Gabriel Alameh, Drew Weissman, Charalampos Papachristou, Jason P Gleghorn, Rachel S Riley.

  Ionizable lipid nanoparticles (LNPs) have gained attention as mRNA delivery platforms for vaccination against COVID-19 and for protein replacement therapies. LNPs enhance mRNA stability, circulation time, cellular uptake, and preferential delivery to specific tissues compared to mRNA with no carrier platform. However, LNPs are only in the beginning stages of development for safe and effective mRNA delivery to the placenta to treat placental dysfunction. Here, we develop LNPs that enable high levels of mRNA delivery to trophoblasts in vitro and to the placenta in vivo with no toxicity. We conducted a Design of Experiments to explore how LNP composition, including the type and molar ratio of each lipid component, drives trophoblast and placental delivery. Our data revealed that utilizing C12-200 as the ionizable lipid and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as the phospholipid in the LNP design yields high transfection efficiency in vitro. Analysis of lipid molar composition as a design parameter in LNPs displayed a strong correlation between apparent pKa and poly (ethylene) glycol (PEG) content, as a reduction in PEG molar amount increases apparent pKa. Further, we present one LNP platform that exhibits the highest delivery of placental growth factor mRNA to the placenta in pregnant mice, resulting in synthesis and secretion of a potentially therapeutic protein. Lastly, our high-performing LNPs have no toxicity to both the pregnant mice and fetuses. Our results demonstrate the feasibility of LNPs as a platform for mRNA delivery to the placenta, and our top LNP formulations may provide a therapeutic platform to treat diseases that originate from placental dysfunction during pregnancy.

Keywords:  Drug delivery; Lipid nanoparticles (LNPs); Nucleic acids; Placenta; Placental growth factor (PlGF); Preeclampsia; Pregnancy

DOI:  https://doi.org/10.1016/j.bioactmat.2023.11.014
ACS Appl Bio Mater. 2024 Jan 18.

Lipid- and Polymer-Based Nanocarrier Platforms for Cancer Vaccine Delivery.

Suhair Sunoqrot, Sara A Abdel Gaber, Razan Abujaber, May Al-Majawleh, Shahd Talhouni.

  Cancer immunotherapy has gained popularity in recent years in the search for effective treatment modalities for various malignancies, particularly those that are resistant to conventional chemo- and radiation therapy. Cancer vaccines target the cancer-immunity cycle by boosting the patient's own immune system to recognize and kill cancer cells, thus serving as both preventative and curative therapeutic tools. Among the different types of cancer vaccines, those based on nanotechnology have shown great promise in advancing the field of cancer immunotherapy. Lipid-based nanoparticles (NPs) have become the most advanced platforms for cancer vaccine delivery, but polymer-based NPs have also received considerable interest. This Review aims to provide an overview of the nanotechnology-enabled cancer vaccine landscape, focusing on recent advances in lipid- and polymer-based nanovaccines and their hybrid structures and discussing the challenges against the clinical translation of these important nanomedicines.

Keywords:  cancer immunotherapy; cancer vaccines; lipid nanoparticles; lipid/polymer hybrid nanoparticles; polymeric nanoparticles

DOI:  https://doi.org/10.1021/acsabm.3c00843
Iran J Basic Med Sci. 2024 ;27(2): 122-133

Recent advances in molecular targeted therapy of lung cancer: Possible application in translation medicine.

Elnaz Salmani-Javan, Mahdi Farhoudi Sefidan Jadid, Nosratollah Zarghami.

  Lung cancer is one of the leading causes of death among all cancer deaths. This cancer is classified into two different histological subtypes: non-small cell lung cancer (NSCLC), which is the most common subtype, and small cell lung cancer (SCLC), which is the most aggressive subtype. Understanding the molecular characteristics of lung cancer has expanded our knowledge of the cellular origins and molecular pathways affected by each of these subtypes and has contributed to the development of new therapies. Traditional treatments for lung cancer include surgery, chemotherapy, and radiotherapy. Advances in understanding the nature and specificity of lung cancer have led to the development of immunotherapy, which is the newest and most specialized treatment in the treatment of lung cancer. Each of these treatments has advantages and disadvantages and causes side effects. Today, combination therapy for lung cancer reduces side effects and increases the speed of recovery. Despite the significant progress that has been made in the treatment of lung cancer in the last decade, further research into new drugs and combination therapies is needed to extend the clinical benefits and improve outcomes in lung cancer. In this review article, we discussed common lung cancer treatments and their combinations from the most advanced to the newest.

Keywords:  Combination therapy; Immunotherapy; Lung cancer; Molecular targeted therapy; Translational medicine

DOI:  https://doi.org/10.22038/IJBMS.2023.72407.15749
Adv Healthc Mater. 2024 Jan 17. e2303186

Induced Self-Assembly of Vitamin E-Spermine/Sirna Nanocomplexes via Spermine/Helix Groove-Specific Interaction for Efficient Sirna Delivery and Antitumor Therapy.

Xiaoran Zhao, Qi Xu, Qian Wang, XingXing Liang, Jing Wang, Hongwei Jin, Yizhi Man, Dongyang Guo, Feng Gao, Xinjing Tang.

  Gene therapy has been one of potential strategies for the treatment of different diseases, where efficient and safe gene delivery systems are also extremely in need. Current LNP technology highly depends on the packing and condensation of nucleic acids with amine moieties. Here, we attempt to covalently link two natural compounds, spermine and vitamin E, to develop self-assembled nucleic acid delivery systems. Among them, the spermine moieties specifically interact with the major groove of siRNA helix through salt bridge interaction, while vitamin E moieties are located around siRNA duplex. Such amphiphilic vitamin E-spermine/siRNA complexes can further self-assemble into nanocomplexes like multi-blade wheels. Further studies indicate that these siRNA nanocomplexes with the neutrally charged surface of vitamin E can enter cells via caveolin/lipid raft mediated endocytosis pathway and bypass lysosome trapping. With these self-assembled delivery systems, we successfully achieve efficient siRNA delivery for Eg5 and Survivin gene silencing as well as DNA plasmid delivery. Further in vivo study indicate that VE-Su-Sper/DSPE-PEG2000 /siSurvivin self-assembled nanocomplexes can accumulate in cancer cells and gradually release siRNA in tumor tissues and show significant antitumor effect in vivo. The self-assembled delivery system provides a novel strategy for highly efficient siRNA delivery. This article is protected by copyright. All rights reserved.

Keywords:  gene delivery; lysosome escape; self-assembly; siRNA; vitamin E

DOI:  https://doi.org/10.1002/adhm.202303186
Macromol Biosci. 2024 Jan 16. e2300366

Recent Progress in the Endosomal Escape Mechanism and Chemical Structures of Polycations for Nucleic Acid Delivery.

Mohit J Mehta, Hyun Jin Kim, Sung Been Lim, Mitsuru Naito, Kanjiro Miyata.

  Nucleic acid-based therapies are seeing a spiralling surge. Stimuli-responsive polymers, especially pH-responsive ones, are gaining widespread attention because of their ability to efficiently deliver nucleic acids. These polymers can be synthesized and modified according to target requirements, such as delivery sites and the nature of nucleic acids. In this regard, the endosomal escape mechanism of polymer-nucleic acid complexes (polyplexes) remains a topic of considerable interest owing to various plausible escape mechanisms. This review describes current progress in the endosomal escape mechanism of polyplexes and state-of-the-art chemical designs for pH-responsive polymers. The importance is also discussed of the acid dissociation constant (i.e., pKa ) in designing the new generation of pH-responsive polymers, along with assays to monitor and quantify the endosomal escape behavior. Further, the use of machine learning is addressed in pKa prediction and polymer design to find novel chemical structures for pH responsiveness. This review will facilitate the design of new pH-responsive polymers for advanced and efficient nucleic acid delivery.

Keywords:  acid dissociation constant; mRNAnucleic acid delivery; polyplex; siRNA

DOI:  https://doi.org/10.1002/mabi.202300366
ACS Macro Lett. 2024 Jan 17. 158-165

Tailoring Gene Transfer Efficacy through the Arrangement of Cationic and Anionic Blocks in Triblock Copolymer Micelles.

Katharina Leer, Liên S Reichel, Mara Wilhelmi, Johannes C Brendel, Anja Traeger.

The arrangement of charged segments in triblock copolymer micelles affects the gene delivery potential of polymeric micelles and can increase the level of gene expression when an anionic segment is incorporated in the outer shell. Triblock copolymers were synthesized by RAFT polymerzation with narrow molar mass distributions and assembled into micelles with a hydrophobic core from poly(n-butyl acrylate). The ionic shell contained either (i) an anionic segment followed by a cationic segment (HAC micelles) or (ii) a cationic block followed by an anionic block (HCA micelles). The pH-responsive anionic block contained 2-carboxyethyl acrylamide (CEAm), while the cationic block comprised 3-guanidinopropyl acrylamide (GPAm). Increasing the molar content of CEAm in HAC and HCA micelles from 6 to 13 mol % improved cytocompatibility and the endosomal escape property, while the HCA micelle with the highest mol % of anionic charges in the outer shell exhibited the highest gene expression. It became evident that improved membrane interaction of the best performing HCA micelle contributed to achieving high gene expression.

DOI: https://doi.org/10.1021/acsmacrolett.3c00633
Front Mol Biosci. 2023 ;10 1297413

Advancing cancer treatment: in vivo delivery of therapeutic small noncoding RNAs.

Xiaoyue Yang, Ying Liang, Sheng Tong.

  In recent years, small non-coding RNAs (ncRNAs) have emerged as a new player in the realm of cancer therapeutics. Their unique capacity to directly modulate genetic networks and target oncogenes positions them as valuable complements to existing small-molecule drugs. Concurrently, the advancement of small ncRNA-based therapeutics has rekindled the pursuit of efficacious in vivo delivery strategies. In this review, we provide an overview of the most current clinical and preclinical studies in the field of small ncRNA-based cancer therapeutics. Furthermore, we shed light on the pivotal challenges hindering the successful translation of these promising therapies into clinical practice, with a specific focus on delivery methods, aiming to stimulate innovative approaches to address this foundational aspect of cancer treatment.

Keywords:  cancer; in vivo delivery; miRNA; siRNA; small non-coding RNA

DOI:  https://doi.org/10.3389/fmolb.2023.1297413
Mol Ther. 2024 Jan 18. pii: S1525-0016(24)00020-0. [Epub ahead of print]

Lymph node macrophages drive innate immune responses to enhance the anti-tumor efficacy of mRNA vaccines.

Kenji Kubara, Kazuto Yamazaki, Takayuki Miyazaki, Keita Kondo, Daisuke Kurotaki, Tomohiko Tamura, Yuta Suzuki.

mRNA vaccines are promising for cancer treatment. Efficient delivery of mRNAs encoding tumor antigens to antigen-presenting cells (APCs) is critical to elicit anti-tumor immunity. Herein, we identified a novel lipid nanoparticle (LNP) formulation, L17-F05, for mRNA vaccines by screening 34 ionizable lipids and 28 LNP formulations using human primary APCs. Subcutaneous delivery of L17-F05 mRNA vaccine encoding Gp100 and Trp2 inhibited tumor growth and prolonged the survival of mice bearing B16F10 melanoma. L17-F05 efficiently delivered mRNAs to conventional dendritic cells (cDCs) and macrophages in draining lymph nodes (dLNs). cDCs functioned as the main APCs by presenting antigens along with enhanced expression of co-stimulatory molecules. Macrophages triggered innate immune responses centered on type-I interferon (IFN-I) in dLNs. Lymph node (LN) macrophage depletion attenuated APC maturation and anti-tumor activity of L17-F05 mRNA vaccines. Loss-of-function studies revealed that L17-F05 works as a self-adjuvant by activating the stimulator of interferon genes (STING) pathway in macrophages. Collectively, the self-adjuvanticity of L17-F05 triggered innate immune responses in LN macrophages via the STING-IFN-I pathway, contributing to APC maturation and potent anti-tumor activity of L17-F05 mRNA vaccines. Our findings provide strategies for further optimization of mRNA vaccines based on the innate immune response driven by LN macrophages.

DOI: https://doi.org/10.1016/j.ymthe.2024.01.020
Nanoscale Adv. 2024 Jan 16. 6(2): 669-679

Navigating the challenges of lipid nanoparticle formulation: the role of unpegylated lipid surfactants in enhancing drug loading and stability.

Cameron Hogarth, Keith Arnold, Steve Wright, Heba Elkateb, Steve Rannard, Tom O McDonald.

Lipid nanoparticles have proved an attractive approach for drug delivery; however, the challenges of optimising formulation stability and increasing drug loading have limited progression. In this work, we investigate the role of unpegylated lipid surfactants (helper lipids) in nanoparticle formation and the effect of blending helper lipids with pegylated lipid surfactants on the formation and stability of lipid-based nanoparticles by nanoprecipitation. Furthermore, blends of unpegylated/pegylated lipid surfactants were examined for ability to accommodate higher drug loading formulations by means of a higher weight percentage (wt%) of drug relative to total mass of formulation components (i.e. drug, surfactants and lipids). Characterisation included evaluation of particle diameter, size distribution, drug loading and nanoformulation stability. Our findings demonstrate that the addition of unpegylated lipid surfactant (Lipoid S100) to pegylated lipid surfactant (Brij S20) enhances stability, particularly at higher weight percentages of the core material. This blending approach enables drug loading capacities exceeding 10% in the lipid nanoparticles. Notably, Lipoid S100 exhibited nucleating properties that aided in the formation and stabilisation of the nanoparticles. Furthermore, we examined the incorporation of a model drug into the lipid nanoparticle formulations. Blending the model drug with the core material disrupted the crystallinity of the core, offering additional potential benefits in terms of drug release and stability. This comprehensive investigation provides valuable insights into the interplay between surfactant properties, core material composition, and nanoparticle behaviour. The study enhances our understanding of lipid materials and offers guidance for the design and optimisation of lipid nanoparticle formulations.

DOI: https://doi.org/10.1039/d3na00484h