bims-novged 2024-05-12 papers

bims-novged

Biomed News

on Non-viral vectors for gene delivery

Issue of 2024–05–12
ten papers selected by
the Merkel lab, Ludwig-Maximilians University

Cationic Lipid Pairs Enhance Liver-to-Lung Tropism of Lipid Nanoparticles for In Vivo mRNA Delivery.
Chemical Design Strategy of Ionizable Lipids for In Vivo mRNA Delivery.
The impact of, and expectations for, lipid nanoparticle technology: From cellular targeting to organelle targeting.
Long-term stability and immunogenicity of lipid nanoparticle COVID-19 mRNA vaccine is affected by particle size.
Targeted modulation of gene expression through receptor-specific delivery of small interfering RNA peptide conjugates.
A Virus-Inspired Inhalable Liponanogel Induces Potent Antitumor Immunity and Regression in Metastatic Lung Tumors.
Regulation of Protein Conformation Enables Cell-Selective Targeting of Virus-Mimicking Nanoparticles for siRNA Therapy of Glioblastoma.
Co-delivery of paclitaxel and curcumin loaded solid lipid nanoparticles for improved targeting of lung cancer: In vitro and in vivo investigation.
Preparation of Chitosan Nanoparticles through a Readily Solvent-Exchange Process for Efficient and Enhanced Gene Delivery.
Targeting pentamidine towards CD44-overexpressing cells using hyaluronated lipid-polymer hybrid nanoparticles.

ACS Appl Mater Interfaces. 2024 May 08.

Cationic Lipid Pairs Enhance Liver-to-Lung Tropism of Lipid Nanoparticles for In Vivo mRNA Delivery.

Gege Zeng, Zepeng He, Haihong Yang, Zhan Gao, Xueer Ge, Lixin Liu, Zhijia Liu, Yongming Chen.

  Much of current clinical interest has focused on mRNA therapeutics for the treatment of lung-associated diseases, such as infections, genetic disorders, and cancers. However, the safe and efficient delivery of mRNA therapeutics to the lungs, especially to different pulmonary cell types, is still a formidable challenge. In this paper, we proposed a cationic lipid pair (CLP) strategy, which utilized the liver-targeted ionizable lipid and its derived quaternary ammonium lipid as the CLP to improve liver-to-lung tropism of four-component lipid nanoparticles (LNPs) for in vivo mRNA delivery. Interestingly, the structure-activity investigation identified that using liver-targeted ionizable lipids with higher mRNA delivery performance and their derived lipid counterparts is the optimal CLP design for improving lung-targeted mRNA delivery. The CLP strategy was also verified to be universal and suitable for clinically available ionizable lipids such as SM-102 and ALC-0315 to develop lung-targeted LNP delivery systems. Moreover, we demonstrated that CLP-based LNPs were safe and exhibited potent mRNA transfection in pulmonary endothelial and epithelial cells. As a result, we provided a powerful CLP strategy for shifting the mRNA delivery preference of LNPs from the liver to the lungs, exhibiting great potential for broadening the application scenario of mRNA-based therapy.

Keywords:  ionizable lipids; lipid nanoparticles; lung-targeted delivery; mRNA delivery; quaternary ammonium lipids

DOI:  https://doi.org/10.1021/acsami.4c02415
ChemMedChem. 2024 May 09. e202400199

Chemical Design Strategy of Ionizable Lipids for In Vivo mRNA Delivery.

Zepeng He, Zhijia Liu, Yongming Chen.

  Lipid nanoparticles (LNPs) are the most clinically successful drug delivery systems that have accelerated the development of mRNA drugs and vaccines. Among various structural components of LNPs, more recent attention has been paid in ionizable lipids (ILs) that was supposed as the key component in determining the effectiveness of LNPs for in vivo mRNA delivery. ILs are typically comprised of three moieties including ionizable heads, linkers, and hydrophobic tails, which suggested that the combination of different functional groups in three moieties could produce ILs with diverse chemical structures and biological identities. In this concept article, we provide a summary of chemical design strategy for high-performing IL candidates and discuss their structure-activity relationships for shifting tissue-selective mRNA delivery. We also propose an outlook for the development of next-generation ILs, enabling the broader translation of mRNA formulated with LNPs.

Keywords:  chemical design; ionizable lipids; lipid nanoparticles; mRNA delivery; tissue selectivity

DOI:  https://doi.org/10.1002/cmdc.202400199
J Control Release. 2024 May 09. pii: S0168-3659(24)00290-6. [Epub ahead of print]370 516-527

The impact of, and expectations for, lipid nanoparticle technology: From cellular targeting to organelle targeting.

Yusuke Sato, Takashi Nakamura, Yuma Yamada, Hideyoshi Harashima.

  The success of mRNA vaccines against COVID-19 has enhanced the potential of lipid nanoparticles (LNPs) as a system for the delivery of mRNA. In this review, we describe our progress using a lipid library to engineer ionizable lipids and promote LNP technology from the viewpoints of safety, controlled biodistribution, and mRNA vaccines. These advancements in LNP technology are applied to cancer immunology, and a potential nano-DDS is constructed to evaluate immune status that is associated with a cancer-immunity cycle that includes the sub-cycles in tumor microenvironments. We also discuss the importance of the delivery of antigens and adjuvants in enhancing the cancer-immunity cycle. Recent progress in NK cell targeting in cancer immunotherapy is also introduced. Finally, the impact of next-generation DDS technology is explained using the MITO-Porter membrane fusion-based delivery system for the organelle targeting of the mitochondria. We introduce a successful example of the MITO-Porter used in a cell therapeutic strategy to treat cardiomyopathy.

Keywords:  Cancer immunotherapy; Cell therapy; Ionizable lipid; Mitochondria; NK cells; RNA delivery

DOI:  https://doi.org/10.1016/j.jconrel.2024.05.006
Hum Vaccin Immunother. 2024 Dec 31. 20(1): 2342592

Long-term stability and immunogenicity of lipid nanoparticle COVID-19 mRNA vaccine is affected by particle size.

Ruimeng Shi, Xueli Liu, Yajuan Wang, Meilu Pan, Shaoqin Wang, Lin Shi, Beibei Ni.

  Messenger ribonucleic acid (mRNA) technology has been rapidly applied for the development of the COVID-19 vaccine. However, naked mRNA itself is inherently unstable. Lipid nanoparticles (LNPs) protect mRNAs from extracellular ribonucleases and facilitate mRNA trafficking. For mRNA vaccines, antigen-presenting cells utilize LNPs through uptake to elicit antigen-specific immunity. There are reports on the impact of various physical characteristics of LNPs, particularly those with sizes less than 200 nm, especially 50 to 150 nm, on the overall stability and protective efficacy of mRNA vaccines. To address this, a single change in the size of LNPs using the same mRNA stock solution was assessed for the physicochemical characterization of the resulting mRNA-LNPs vaccine, along with the evaluation of their protective efficacy. Particles of smaller sizes generally disperse more effectively in solutions, with minimized occurrence of particle precipitation and aggregation. Here, we demonstrate that the vaccine containing 80-100 nm mRNA-LNPs showed the best stability and protection at 4°C and -20°C. Furthermore, we can conclude that freezing the vaccine at -20°C is more appropriate for maintaining stability over the long term. This effort is poised to provide a scientific basis for improving the quality of ongoing mRNA vaccine endeavors and providing information on the development of novel products.

Keywords:  SARS-CoV-2; biological activity; lipid nanoparticle; mRNA vaccine; particle size; stability

DOI:  https://doi.org/10.1080/21645515.2024.2342592
J Pept Sci. 2024 May 07. e3611

Targeted modulation of gene expression through receptor-specific delivery of small interfering RNA peptide conjugates.

Mareike Schenk, Karin Mörl, Stephan Herzig, Annette G Beck-Sickinger.

  Small interfering RNA (siRNA) has emerged as a valuable tool to address RNA interference (RNAi) to modulate gene expression also in therapy. However, challenges such as inefficient cell targeting and rapid degradation in biological systems have limited its success. To address these issues, the development of a receptor-specific shuttle system represents a promising solution. [F7,P34]-NPY analogues were modified by solid-phase peptide synthesis, enabling non-covalent conjugation with siRNA. This modification yielded an efficient siRNA vehicle capable of binding and transporting its cargo into target cells without adversely affecting receptor activation or cell viability. Mass spectrometry and gel shift assays confirmed successful and stable siRNA binding under various conditions. Microscopy experiments further demonstrated the co-internalization of labeled peptides and siRNA in Hepa1c1 cells, highlighting the stability of the complex. In vitro quantitative RT-PCR experiments, targeting the TSC22D4 gene to normalize systemic glucose homeostasis and insulin resistance, revealed a functional peptide-based siRNA shuttle system with the ability to decrease mRNA expression to approximately 40%. These findings strengthen the potential of receptor-specific siRNA shuttle systems as efficient tools for gene therapy that offer a possibility for reducing side effects.

Keywords:  biological activity; drug delivery; gene expression; oligonucleotides; peptides; receptors; siRNA

DOI:  https://doi.org/10.1002/psc.3611
Cancer Res. 2024 May 08.

A Virus-Inspired Inhalable Liponanogel Induces Potent Antitumor Immunity and Regression in Metastatic Lung Tumors.

Junyao Li, Lanqing Luo, Jia He, Jinchao Yu, Xinyan Li, Xueying Shen, Junxia Zhang, Sai Li, Jeffrey M Karp, Rui Kuai.

Pulmonary delivery of immunostimulatory agents such as poly(I:C) to activate double-stranded RNA sensors MDA5 and RIG-I within lung-resident antigen-presenting cells is a potential strategy to enhance antitumor immunity by promoting type I interferon secretion. However, following pulmonary delivery, poly(I:C) suffers from rapid degradation and poor endosomal escape, thus limiting its potency. Inspired by the structure of a virus that utilizes internal viral proteins to tune the loading and cytosolic delivery of viral nucleic acids, we developed a liponanogel (LNG)-based platform to overcome the delivery challenges of poly(I:C). The LNG consisted of an anionic polymer hyaluronic acid-based nanogel core coated by a lipid shell, which served as a protective layer to stabilize the nanogel core in the lungs. The nanogel core was protonated within acidic endosomes to enhance the endosomal membrane permeability and cytosolic delivery of poly(I:C). After pulmonary delivery, LNG-poly(I:C) induced 13.7-fold more IFNβ than poly(I:C) alone and 2-fold more than poly(I:C) loaded in the state-of-art lipid nanoparticles (LNP-poly(I:C)). Moreover, LNG-poly(I:C) induced more potent CD8+ T cell immunity and stronger therapeutic effects than LNP-poly(I:C). The combination of LNG-poly(I:C) and PD-L1 targeting led to regression of established lung metastases. Due to the ease of manufacturing and the high biocompatibility of LNG, pulmonary delivery of LNG may be broadly applicable to the treatment of different lung tumors and may spur the development of innovative strategies for cancer immunotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3414
Adv Mater. 2024 May 06. e2401640

Regulation of Protein Conformation Enables Cell-Selective Targeting of Virus-Mimicking Nanoparticles for siRNA Therapy of Glioblastoma.

Han Zhu, Yi-Fan Wang, Zhi-Gang Wang, Dai-Wen Pang, Shu-Lin Liu.

  Orthotopic glioblastoma (GBM) has an aggressive growth pattern and complex pathogenesis, becoming one of the most common and deadly tumors of the central nervous system (CNS). The emergence of RNA therapies offers promise for the treatment of GBM. However, the efficient and precise delivery of RNA drugs to specific tumor cells in the brain with high cellular heterogeneity remains ongoing. Here, a strategy is proposed to regulate protein conformation through lipid nanoenvironments to custom-design virus-mimicking nanoparticles (VMNs) with excellent selective cell targeting capabilities, leading to efficient and precise delivery of small interfering RNA for effective treatment of GBM. The optimized VMNs not only retain the ability to cross the blood-brain barrier and release the RNA by lysosomal escape like natural viruses but also ensure precise enrichment in the GBM area. This study lays the conceptual foundation for the custom design of VMNs with superior cell-selective targeting capabilities and opens up the possibility of RNA therapies for the efficient treatment of GBM and CNS tumors.

Keywords:  cell‐selective target; glioblastoma therapy; lipid regulation of protein conformation; siRNA delivery; virus‐mimicking nanoparticles

DOI:  https://doi.org/10.1002/adma.202401640
Heliyon. 2024 May 15. 10(9): e30290

Co-delivery of paclitaxel and curcumin loaded solid lipid nanoparticles for improved targeting of lung cancer: In vitro and in vivo investigation.

Mao Li, Gang Fang, Fatima Zahid, Raheela Saleem, Ghazala Ishrat, Zakir Ali, Muhammad Naeem, Fakhar Ud Din.

  The objective of this study was to develop nanotechnology-mediated paclitaxel (PAC) and curcumin (CUR) co-loaded solid lipid nanoparticles (PAC-CUR-SLNs) for the treatment of lung cancer, which is a leading cause of death worldwide. Around 85 % cases of lungs cancer constitute non-small cell lung cancer (NSCLC). PAC-CUR-SLNs were prepared via high pressure homogenization. The in vitro drug release of PAC-CUR-SLNs was checked followed by their in vitro cytotoxic investigation using adenocarcinomic human alveolar basal epithelial cells (A549) cell lines. Anticancer effects along with side effects of the synergistic delivery of PAC-CUR-SLNs were studied in vivo, using BALB/c mice. PAC-CUR-SLNs were nano sized (190 nm), homogeneously disseminated particles with %IE of both PAC and CUR above 94 %. PAC-CUR-SLNs released PAC and CUR in a controlled fashion when compared with free drug suspensions. The cytotoxicity of PAC-CUR-SLNs was higher than individual drug-loaded SLNs and pure drugs. Moreover, the co-delivery displayed synergistic effect, indicating potential of PAC-CUR-SLNs in lung cancer treatment. In vivo tumor investigation of PAC-CUR-SLNs exhibited 12-fold reduced tumor volume and almost no change in body weight of BALB/c mice, when compared with the experimental groups including control group. The inhibition of tumor rate on day 28 was 82.7 % in the PAC-CUR-SLNs group, which was significantly higher than the pure drugs and monotherapies. It can be concluded that, encapsulating the co-loaded antitumor drugs like PAC-CUR in SLNs may help in improved targeting of the tumor with enhanced anticancer effect.

Keywords:  Combination therapy; Curcumin; Drug delivery; Lung cancer; Nanotechnology; Paclitaxel; Solid lipid nanoparticles

DOI:  https://doi.org/10.1016/j.heliyon.2024.e30290
Langmuir. 2024 May 10.

Preparation of Chitosan Nanoparticles through a Readily Solvent-Exchange Process for Efficient and Enhanced Gene Delivery.

Jialuo Zhang, Shujing Liu, Yulin Wang, Xiaoxu Li, Huazhang Zeng, Boxuan Li, Juan Wang.

In view of the excellent prospects of gene therapy and the potential safety and immunogenicity issues challenged by viral vectors, it is of great significance to develop a nonviral vector with low toxicity and low cost. In this work, we report a chitosan nanoparticle (CSNP) to be used as a gene vector prepared through a facile solvent-exchange strategy. Chitosan is first dissolved in ionic liquid 1-ethyl-3-methylimidazolium acetate (EMIM Ac), and then, the solvent is exchanged with water/phosphate-buffered saline (PBS) to remove ionic liquid, forming a final CSNP dispersion after ultrasonication. The prepared CSNP shows a positive surface charge and can condense green fluorescent protein-encoding plasmid (pGFP) at weight ratios (CSNP/pGFP) of 5/1 or higher. Dynamic light scattering size and ζ-potential characterization and gel retardation results confirm the formation of CSNP/pGFP complexes. Compared with plain pGFP, efficient cellular internalization and significantly enhanced green fluorescent protein (GFP) expression are observed by using CSNP as a plasmid vector. Benefitting from the intrinsic biocompatibility, low cost, low immunogenicity, and abundant sources of chitosan, as well as the facile preparation and the efficient gene transfection capacity of CSNP, it is believed that this CSNP could be used as a nonviral gene vector with great clinical translational potentials.

DOI: https://doi.org/10.1021/acs.langmuir.3c03874
Drug Deliv Transl Res. 2024 May 06.

Targeting pentamidine towards CD44-overexpressing cells using hyaluronated lipid-polymer hybrid nanoparticles.

Ilaria Andreana, Marta Chiapasco, Valeria Bincoletto, Sabrina Digiovanni, Maela Manzoli, Caterina Ricci, Elena Del Favero, Chiara Riganti, Silvia Arpicco, Barbara Stella.

  Biodegradable nanocarriers possess enormous potential for use as drug delivery systems that can accomplish controlled and targeted drug release, and a wide range of nanosystems have been reported for the treatment and/or diagnosis of various diseases and disorders. Of the various nanocarriers currently available, liposomes and polymer nanoparticles have been extensively studied and some formulations have already reached the market. However, a combination of properties to create a single hybrid system can give these carriers significant advantages, such as improvement in encapsulation efficacy, higher stability, and active targeting towards specific cells or tissues, over lipid or polymer-based platforms. To this aim, this work presents the formulation of poly(lactic-co-glycolic) acid (PLGA) nanoparticles in the presence of a hyaluronic acid (HA)-phospholipid conjugate (HA-DPPE), which was used to anchor HA onto the nanoparticle surface and therefore create an actively targeted hybrid nanosystem. Furthermore, ionic interactions have been proposed for drug encapsulation, leading us to select the free base form of pentamidine (PTM-B) as the model drug. We herein report the preparation of hybrid nanocarriers that were loaded via ion-pairing between the negatively charged PLGA and HA and the positively charged PTM-B, demonstrating an improved loading capacity compared to PLGA-based nanoparticles. The nanocarriers displayed a size of below 150 nm, a negative zeta potential of -35 mV, a core-shell internal arrangement and high encapsulation efficiency (90%). Finally, the ability to be taken up and exert preferential and receptor-mediated cytotoxicity on cancer cells that overexpress the HA specific receptor (CD44) has been evaluated. Competition assays supported the hypothesis that PLGA/HA-DPPE nanoparticles deliver their cargo within cells in a CD44-dependent manner.

Keywords:  Hyaluronic acid; Lipid-polymer hybrid nanoparticles; PLGA; Pentamidine; Phospholipid conjugate

DOI:  https://doi.org/10.1007/s13346-024-01617-7