bims-novged Biomed News
on Non-viral vectors for gene delivery
Issue of 2023–09–03
nine papers selected by
the Merkel lab, Ludwig-Maximilians University
  1. Enhancing the Gene Transfection of Poly(β-amino ester)/DNA Polyplexes by Modular Manipulation of Amphiphilicity.
  2. Repositioning the over-the-counter antihistamine ebastine as an intracellular siRNA delivery enhancer.
  3. Stimuli-Responsive Non-viral Nanoparticles for Gene Delivery.
  4. Targeting oncogenic KRAS in non-small cell lung cancer with EGFR aptamer-conjugated multifunctional RNA nanoparticles.
  5. A Unified Strategy to Improve Lipid Nanoparticle Mediated mRNA Delivery Using Adenosine Triphosphate.
  6. RNAi therapies: Expanding applications for extrahepatic diseases and overcoming delivery challenges.
  7. Targeting materials and strategies for RNA delivery.
  8. Pulmonary delivery of mucus-traversing PF127-modified silk fibroin nanoparticles loading with quercetin for lung cancer therapy.
  9. Microfluidics for nano-drug delivery systems: From fundamentals to industrialization.
  1. ACS Appl Mater Interfaces. 2023 Aug 29.
    Enhancing the Gene Transfection of Poly(β-amino ester)/DNA Polyplexes by Modular Manipulation of Amphiphilicity.
    Jiahao Shi, Yuhe Zhang, Bin Ma, Haiyang Yong, Delu Che, Chaolan Pan, Wei He, Dezhong Zhou, Ming Li.
      Poly(β-amino ester)s (PAEs) have been widely developed for gene delivery, and hydrophobic modification can further enhance their gene transfection efficiency. However, systematic manipulation of amphiphilicity of PAEs through copolymerization with hydrophobic monomers is time-consuming and, to some extent, uncontrollable. Here, a modular strategy is developed to manipulate the amphiphilicity of the PAE/DNA polyplexes. A hydrophobic polymer (DD-C12-122) and a hydrophilic polymer (DD-90-122) are synthesized separately and used as a hydrophobic module and a hydrophilic module, respectively. The amphiphilicity of polyplexes could be manipulated by changing the ratio of the hydrophobic module and hydrophilic module. Using the modular strategy, the PAE/DNA polyplexes with the highest gene transfection efficiency and safety profile as well as possible mechanisms are identified. The modular strategy provides a novel way to engineer the hydrophobicity of PAEs to improve their gene transfection and can be easily generalized and potentially extended to other polymeric gene delivery systems.
    Keywords:  amphiphilicity; gene transfection; modular strategy; poly(β-amino ester)s; transfection activity
    DOI:  https://doi.org/10.1021/acsami.3c03802
  2. Int J Pharm. 2023 Aug 24. pii: S0378-5173(23)00768-8. [Epub ahead of print] 123348
    Repositioning the over-the-counter antihistamine ebastine as an intracellular siRNA delivery enhancer.
    Cristina Muntean, Eva Blondeel, Laure Harinck, Kunal Pednekar, Jai Prakash, Olivier De Wever, Jeanne Leblond Chain, Stefaan C De Smedt, Katrien Remaut, Koen Raemdonck.
      Small interfering RNAs (siRNAs) are promising therapeutics for the treatment of human diseases via the induction of sequence-specific gene silencing. To be functional, siRNAs require cytosolic delivery into target cells. However, state-of-the-art delivery systems mediate cellular entry through endocytosis and suffer from ineffective endosomal escape, routing a substantial fraction of the siRNA towards the lysosomal compartment. Cationic amphiphilic drugs (CADs) have been described to improve cytosolic siRNA delivery by the transient induction of lysosomal membrane permeabilization. In this work, we evaluated ebastine, an over-the-counter antihistamine CAD, for its ability to enhance cytosolic release of siRNA in a non-small cell lung cancer model. In particular, we demonstrate that ebastine can improve the siRNA-mediated gene silencing efficiency of a polymeric nanogel by 40-fold, outperforming other CAD compounds. Additionally, ebastine substantially enhanced gene knockdown of a cholesterol-conjugated siRNA, in two-dimensional (2D) cell culture as well as in three-dimensional (3D) tumor spheroids. Finally, ebastine could strongly promote siRNA delivery of lipid nanoparticles (LNPs) composed of a pH-dependent switchable ionizable lipid and with stable PEGylation, in contrast to state-of-the-art LNP formulations. Altogether, we identified ebastine as a potent and versatile siRNA delivery enhancer in cancer cells, which offers opportunities for drug combination therapy in oncology.
    DOI:  https://doi.org/10.1016/j.ijpharm.2023.123348
  3. Handb Exp Pharmacol. 2023 Aug 30.
    Stimuli-Responsive Non-viral Nanoparticles for Gene Delivery.
    Liên S Reichel, Anja Traeger.
      Considering nucleic acids as the language of life and the genome as the instruction manual of cells, their targeted modulation promises great opportunities in treating and healing diseases. In addition to viral gene transfer, the overwhelming power of non-viral mRNA-based vaccines is driving the development of novel gene transporters. Thereby, various nucleic acids such as DNA (pDNA) or RNA (mRNA, siRNA, miRNA, gRNA, or ASOs) need to be delivered, requiring a transporter due to their high molar mass and negative charge in contrast to classical agents. This chapter presents the specific biological hurdles for using nucleic acids and shows how new materials can overcome these.
    Keywords:  Gene delivery; Gene therapy; Lipid; Nanomedicine; Non-viral; Polymer; Vaccination
    DOI:  https://doi.org/10.1007/164_2023_694
  4. Mol Ther Nucleic Acids. 2023 Sep 12. 33 559-571
    Targeting oncogenic KRAS in non-small cell lung cancer with EGFR aptamer-conjugated multifunctional RNA nanoparticles.
    Linlin Yang, Zhefeng Li, Daniel W Binzel, Peixuan Guo, Terence M Williams.
      KRAS mutations are one of the most common oncogenic driver mutations in human cancers, including non-small cell lung cancer (NSCLC), and have established roles in cancer pathogenesis and therapeutic resistance. The development of effective inhibitors of mutant KRAS represents a significant challenge. Three-way junction (3WJ)-based multi-functional RNA nanoparticles have the potential to serve as an effective in vivo siRNA delivery platform with the ability to enhance tumor targeting specificity and visualize biodistribution through an imaging moiety. Herein, we assembled novel EGFRapt-3WJ-siKRASG12C mutation targeted nanoparticles to target EGFR-expressing human NSCLC harboring a KRASG12C mutation to silence KRASG12C expression in a tumor cell-specific fashion. We found that EGFRapt-3WJ-siKRASG12C nanoparticles potently depleted cellular KRASG12C expression, resulting in attenuation of downstream MAPK pathway signaling, cell proliferation, migration/invasion ability, and sensitized NSCLC cells to chemoradiotherapy. In vivo, these nanoparticles induced tumor growth inhibition in KRASG12C NSCLC tumor xenografts. Together, this study suggests that the 3WJ pRNA-based platform has the potential to suppress mutant KRAS activity for the treatment of KRAS-driven human cancers, and warrants further development for clinical translation.
    Keywords:  3WJ; EGFR RNA aptamer; KRASG12C; MT: Delivery Strategies; NSCLC; RNA nanotechnology; non-small cell lung cancer; pRNA; siRNA; three-way junction
    DOI:  https://doi.org/10.1016/j.omtn.2023.07.027
  5. J Am Chem Soc. 2023 Sep 01.
    A Unified Strategy to Improve Lipid Nanoparticle Mediated mRNA Delivery Using Adenosine Triphosphate.
    Yutian Ma, Owen S Fenton.
      A central goal of chemical and drug delivery sciences is to maximize the therapeutic efficacy of a given drug at the lowest possible dose. Here, we report a generalizable strategy that can be utilized to improve the delivery of mRNA drugs using lipid nanoparticles (LNPs), the clinically approved chemistry platforms utilized in the Moderna and Pfizer/BioNTech COVID-19 vaccines. In brief, our strategy updates the chemistry of LNPs to incorporate adenosine triphosphate (ATP) alongside mRNA, a modification that results in upward of a 79-fold increase in LNP-delivered mRNA-encoded protein expression in vitro and a 24-fold increase in vivo when compared to parent mRNA LNP formulations that do not contain ATP. Notably, we find that our ATP co-delivery strategy increases LNP-delivered mRNA-encoded protein expression across eight different LNP chemistries and three different cell lines, under normoxia and hypoxia, and in a well-tolerated fashion. Notably, our strategy also improves the expression of mRNA encoding for intracellular and secreted proteins both in vitro and in vivo, highlighting the utility of leveraging ATP co-delivery within mRNA LNPs as a means to increase protein expression. In developing this strategy, we hope that we have provided a simple yet powerful approach to improving mRNA LNPs that may one day be useful in developing therapies for human disease.
    DOI:  https://doi.org/10.1021/jacs.3c05574
  6. Adv Drug Deliv Rev. 2023 Aug 30. pii: S0169-409X(23)00388-5. [Epub ahead of print] 115073
    RNAi therapies: Expanding applications for extrahepatic diseases and overcoming delivery challenges.
    Jong Won Lee, Man Kyu Shim, Hyosuk Kim, Hochung Jang, Yuhan Lee, Sun Hwa Kim.
      The era of RNA medicine has become a reality with the success of messenger RNA (mRNA) vaccines against COVID-19 and the approval of several RNA interference (RNAi) agents in recent years. Particularly, therapeutics based on RNAi offer the promise of targeting intractable and previously undruggable disease genes. Recent advances have focused in developing delivery systems to enhance the poor cellular uptake and insufficient pharmacokinetic properties of RNAi therapeutics and thereby improve its efficacy and safety. However, such approach has been mainly achieved via lipid nanoparticles (LNPs) or chemical conjugation with N-Acetylgalactosamine (GalNAc), thus current RNAi therapy has been limited to liver diseases, most likely to encounter liver-targeting limitations. Hence, there is a huge unmet medical need for intense evolution of RNAi therapeutics delivery systems to target extrahepatic tissues and ultimately extend their indications for treating various intractable diseases. In this review, challenges of delivering RNAi therapeutics to tumors and major organs are discussed, as well as their transition to clinical trials. This review also highlights innovative and promising preclinical RNAi-based delivery platforms for the treatment of extrahepatic diseases.
    Keywords:  Clinical translation; Delivery systems; Gene delivery; Organ-specific targeting; RNA interference
    DOI:  https://doi.org/10.1016/j.addr.2023.115073
  7. Theranostics. 2023 ;13(13): 4667-4693
    Targeting materials and strategies for RNA delivery.
    Lixin Lin, Kexin Su, Qiang Cheng, Shuai Liu.
      RNA-based therapeutics have shown great promise in various medical applications, including cancers, infectious diseases, and metabolic diseases. The recent success of mRNA vaccines for combating the COVID-19 pandemic has highlighted the medical value of RNA drugs. However, one of the major challenges in realizing the full potential of RNA drugs is to deliver RNA into specific organs and tissues in a targeted manner, which is crucial for achieving therapeutic efficacy, reducing side effects, and enhancing overall treatment efficacy. Numerous attempts have been made to pursue targeting, nonetheless, the lack of clear guideline and commonality elucidation has hindered the clinical translation of RNA drugs. In this review, we outline the mechanisms of action for targeted RNA delivery systems and summarize four key factors that influence the targeting delivery of RNA drugs. These factors include the category of vector materials, chemical structures of vectors, administration routes, and physicochemical properties of RNA vectors, and they all notably contribute to specific organ/tissue tropism. Furthermore, we provide an overview of the main RNA-based drugs that are currently in clinical trials, highlighting their design strategies and tissue tropism applications. This review will aid to understand the principles and mechanisms of targeted delivery systems, accelerating the development of future RNA drugs for different diseases.
    Keywords:  RNA-based therapeutics; Specific organ/tissue tropism; Targeting materials; Targeting strategies; mRNA delivery
    DOI:  https://doi.org/10.7150/thno.87316
  8. Asian J Pharm Sci. 2023 Jul;18(4): 100833
    Pulmonary delivery of mucus-traversing PF127-modified silk fibroin nanoparticles loading with quercetin for lung cancer therapy.
    Yu Tang, Lanfang Zhang, Rui Sun, Baiyi Luo, Yu Zhou, Yan Zhang, Yuqi Liang, Bo Xiao, Chenhui Wang.
      The mucosal barrier remains a major barrier in the pulmonary drug delivery system, as mucociliary clearance in the airway accelerates the removal of inhaled nanoparticles (NPs). Herein, we designed and developed the inhalable Pluronic F127-modified silk fibroin NPs loading with quercetin (marked as QR-SF (PF127) NPs), aiming to solve the airway mucus barrier and improve the cancer therapeutic effect of QR. The PF127 coating on the SF NPs could attenuate the interaction between NPs and mucin proteins, thus facilitating the diffusion of SF(PF127) NPs in the mucus layer. The QR-SF (PF127) NPs had particle sizes of approximately 200 nm with negatively charged surfaces and showed constant drug release properties. Fluorescence recovery after photobleaching (FRAP) assay and transepithelial transport test showed that QR-SF (PF127) NPs exhibited superior mucus-penetrating ability in artificial mucus and monolayer Calu-3 cell model. Notably, a large amount of QR-SF (PF127) NPs distributed uniformly in the mice airway section, indicating the good retention of NPs in the respiratory tract. The mice melanoma lung metastasis model was established, and the therapeutic effect of QR-SF (PF127) NPs was significantly improved in vivo. PF127-modified SF NPs may be a promising strategy to attenuate the interaction with mucin proteins and enhance mucus penetration efficiency in the pulmonary drug delivery system.
    Keywords:  Mucus penetration; Pluronic F127; Pulmonary drug delivery; Quercetin
    DOI:  https://doi.org/10.1016/j.ajps.2023.100833
  9. Acta Pharm Sin B. 2023 Aug;13(8): 3277-3299
    Microfluidics for nano-drug delivery systems: From fundamentals to industrialization.
    Huan Zhang, Jie Yang, Rongze Sun, Songren Han, Zhaogang Yang, Lesheng Teng.
      In recent years, owing to the miniaturization of the fluidic environment, microfluidic technology offers unique opportunities for the implementation of nano drug delivery systems (NDDSs) production processes. Compared with traditional methods, microfluidics improves the controllability and uniformity of NDDSs. The fast mixing and laminar flow properties achieved in the microchannels can tune the physicochemical properties of NDDSs, including particle size, distribution and morphology, resulting in narrow particle size distribution and high drug-loading capacity. The success of lipid nanoparticles encapsulated mRNA vaccines against coronavirus disease 2019 by microfluidics also confirmed its feasibility for scaling up the preparation of NDDSs via parallelization or numbering-up. In this review, we provide a comprehensive summary of microfluidics-based NDDSs, including the fundamentals of microfluidics, microfluidic synthesis of NDDSs, and their industrialization. The challenges of microfluidics-based NDDSs in the current status and the prospects for future development are also discussed. We believe that this review will provide good guidance for microfluidics-based NDDSs.
    Keywords:  Industrialization; Lipid nanoparticles; Liposomes; Microfluidics; Nano-drug delivery system; Nanomedicine; Nanoparticles; Physicochemical properties
    DOI:  https://doi.org/10.1016/j.apsb.2023.01.018
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