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Pharmaceutics
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Progress and Innovation on Nanosystems for Gene Therapy
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Progress and Innovation on Nanosystems for Gene Therapy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (20 August 2023) | Viewed by 18534

Special Issue Editors

Dr. Fani Pereira de Sousa

E-Mail Website
Guest Editor
CICS-UBI—Health Science Research Centre, University of Beira Interior, 6200-506 Covilha, Portugal
Interests: biopharmaceuticals; recombinant production; downstream processing; chromatography; gene therapy; gene silencing; health biotechnology
Special Issues, Collections and Topics in MDPI journals
Dr. Joana Valente

E-Mail Website
Guest Editor
Centre for Rapid and Sustainable Product Development, Polytechnic Institute of Leiria, 2430-028 Leiria, Portugal
Interests: additive manufacturing; antimicrobial materials; biomaterials; chromatography; drug delivery systems; gene therapy; tissue engineering
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gene therapy has shown potential for use as a clinical intervention for the treatment of several conditions, including cancer, infectious diseases, neurological pathologies among others. Currently, this therapy is not limited to the delivery of DNA to cells, but it can also consider other nucleic acids, such as small interfering RNA, antisense oligonucleotides, or microRNA, as therapeutic agents. Non-viral vectors, especially nanocarriers, have offered an ideal platform to be applied as gene delivery systems acting as a realistic alternative to viral vectors for achieving better efficacy and safety in gene therapy. Different types of nanocarriers such as liposomes, metallic and polymeric nanoparticles, dendrimers, and quantum dots/rods have been developed, and each shows distinct characteristics. Meanwhile, systemic delivery is a real challenge for these non-viral vectors since they need to survive in the bloodstream without being degraded or captured by cellular defence mechanisms. Also, when reaching the target organ/tissue, the systems must cross the tissue and bind specifically to the target cells. After this internalization process, it is further required to surpass intracellular obstacles, namely by achieving endosomal escape, surpassing cytoplasm traffic, and finally, entering the nucleus. So, the ability of non-viral vectors to overcome these barriers will dictate their efficiency.

Dr. Fani Pereira de Sousa
Dr. Joana Valente
Guest Editors

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Keywords

  • dendrimers
  • gene therapy
  • liposomes
  • mathematical models applied to the nanocarriers production
  • polymeric, ceramic, and metallic nanocarriers

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Published Papers (6 papers)

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Research

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12 pages, 5143 KiB  
Article
Modified mRNA Formulation and Stability for Cardiac and Skeletal Muscle Delivery
by Magdalena M. Żak, Keerat Kaur, Jimeen Yoo, Ann Anu Kurian, Matthew Adjmi, Gayatri Mainkar, Seonghun Yoon and Lior Zangi
Pharmaceutics 2023, 15(9), 2176; https://doi.org/10.3390/pharmaceutics15092176 - 22 Aug 2023
Cited by 4 | Viewed by 2437
Abstract
Directly injecting naked or lipid nanoparticle (LNP)-encapsulated modified mRNA (modRNA) allows rapid and efficient protein expression. This non-viral technology has been used successfully in modRNA vaccines against SARS-CoV-2. The main challenges in using modRNA vaccines were the initial requirement for an ultra-cold storage [...] Read more.
Directly injecting naked or lipid nanoparticle (LNP)-encapsulated modified mRNA (modRNA) allows rapid and efficient protein expression. This non-viral technology has been used successfully in modRNA vaccines against SARS-CoV-2. The main challenges in using modRNA vaccines were the initial requirement for an ultra-cold storage to preserve their integrity and concerns regarding unwanted side effects from this new technology. Here, we showed that naked modRNA maintains its integrity when stored up to 7 days at 4 °C, and LNP-encapsulated modRNA for up to 7 days at room temperature. Naked modRNA is predominantly expressed at the site of injection when delivered into cardiac or skeletal muscle. In comparison, LNP-encapsulated modRNA granted superior protein expression but also additional protein expression beyond the cardiac or skeletal muscle injection site. To overcome this challenge, we developed a skeletal-muscle-specific modRNA translation system (skeletal muscle SMRTs) for LNP-encapsulated modRNA. This system allows controlled protein translation predominantly at the site of injection to prevent potentially detrimental leakage and expression in major organs. Our study revealed the potential of the SMRTs platform for controlled expression of mRNA payload delivered intramuscularly. To conclude, our SMRTs platform for LNP-encapsulated modRNA can provide safe, stable, efficient and targeted gene expression at the site of injection. Full article
(This article belongs to the Special Issue Progress and Innovation on Nanosystems for Gene Therapy)
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20 pages, 26843 KiB  
Article
Lipid Nanoparticles as a Shuttle for Anti-Adipogenic miRNAs to Human Adipocytes
by Anna-Laurence Schachner-Nedherer, Julia Fuchs, Ivan Vidakovic, Oliver Höller, Gebhard Schratter, Gunter Almer, Eleonore Fröhlich, Andreas Zimmer, Martin Wabitsch, Karin Kornmueller and Ruth Prassl
Pharmaceutics 2023, 15(7), 1983; https://doi.org/10.3390/pharmaceutics15071983 - 19 Jul 2023
Cited by 5 | Viewed by 2256
Abstract
Obesity and type 2 diabetes are major health burdens for which no effective therapy is available today. One treatment strategy could be to balance the metabolic functions of adipose tissue by regulating gene expressions using miRNAs. Here, we have loaded two anti-adipogenic miRNAs [...] Read more.
Obesity and type 2 diabetes are major health burdens for which no effective therapy is available today. One treatment strategy could be to balance the metabolic functions of adipose tissue by regulating gene expressions using miRNAs. Here, we have loaded two anti-adipogenic miRNAs (miR26a and miR27a) into a pegylated lipid nanoparticle (PEG-LNP) formulation by a single-step microfluidic-assisted synthesis step. For the miRNA-loaded LNPs, the following system properties were determined: particle size, zeta potential, miRNA complexation efficiency, and cytotoxicity. We have used a human preadipocyte cell line to address the transfection efficiency and biological effects of the miRNA candidates at the gene and protein level. Our findings revealed that the upregulation of miR27a in preadipocytes inhibits adipogenesis by the downregulation of PPARγ and the reduction of lipid droplet formation. In contrast, miR26a transfection in adipocytes induced white adipocyte browning detected as the upregulation of uncoupling protein 1 (UCP1) as a marker of non-shivering thermogenesis. We conclude that the selective delivery of miRNAs by PEG-LNPs to adipocytes could offer new perspectives for the treatment of obesity and related metabolic diseases. Full article
(This article belongs to the Special Issue Progress and Innovation on Nanosystems for Gene Therapy)
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14 pages, 4584 KiB  
Article
Elastin-Derived VGVAPG Fragment Decorated Cell-Penetrating Peptide with Improved Gene Delivery Efficacy
by Wen-Juan Shen, Duo-Mei Tian, Le Fu, Biao Jin, Yu Liu, Yun-Sheng Xu, Yong-Bin Ye, Xiao-Bo Wang, Xiao-Jun Xu, Chun Tang, Fang-Ping Li, Chun-Fei Wang, Gang Wu and Le-Ping Yan
Pharmaceutics 2023, 15(2), 670; https://doi.org/10.3390/pharmaceutics15020670 - 16 Feb 2023
Cited by 6 | Viewed by 2092
Abstract
Cell-penetrating peptides (CPPs) are attractive non-viral gene delivery vectors due to their high transfection capacity and safety. Previously, we have shown that cell-penetrating peptide RALA can be a promising gene delivery vector for chronic wound regeneration application. In this study, we engineered a [...] Read more.
Cell-penetrating peptides (CPPs) are attractive non-viral gene delivery vectors due to their high transfection capacity and safety. Previously, we have shown that cell-penetrating peptide RALA can be a promising gene delivery vector for chronic wound regeneration application. In this study, we engineered a novel peptide called RALA-E by introducing elastin-derived VGVAPG fragment into RALA, in order to target the elastin-binding protein on the cell surface and thus improve delivery efficacy of RALA. The transfection efficiency of RALA-E was evaluated by transfecting the HEK-293T and HeLa cell lines cells with RALA-E/pDNA complexes and the flow-cytometry results showed that RALA-E significantly increased the transfection efficiency by nearly 20% in both cell lines compared to RALA. Inhibition of pDNA transfection on HEK-293T cells via chlorpromazine, genistein and mβCD showed that the inhibition extent in transfection efficiency was much less for RALA-E group compared to RALA group. In addition, RALA-E/miR-146a complexes showed up to 90% uptake efficiency in macrophages, and can escape from the endosome and enter the nucleus to inhibit the expression of inflammation genes. Therefore, the developed RALA-E peptide has high potential as a safe and efficient vector for gene therapy application. Full article
(This article belongs to the Special Issue Progress and Innovation on Nanosystems for Gene Therapy)
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17 pages, 3335 KiB  
Article
Gallic Acid–Triethylene Glycol Aptadendrimers Synthesis, Biophysical Characterization and Cellular Evaluation
by André Miranda, Roi Lopez-Blanco, Jéssica Lopes-Nunes, Ana M. Melo, Maria Paula Cabral Campello, António Paulo, Maria Cristina Oliveira, Jean-Louis Mergny, Paula A. Oliveira, Eduardo Fernandez-Megia and Carla Cruz
Pharmaceutics 2022, 14(11), 2456; https://doi.org/10.3390/pharmaceutics14112456 - 14 Nov 2022
Cited by 4 | Viewed by 2456
Abstract
Herein, we describe the synthesis of an aptadendrimer by covalent bioconjugation of a gallic acid–triethylene glycol (GATG) dendrimer with the G-quadruplex (G4) AT11 aptamer (a modified version of AS1411) at the surface. We evaluated the loading and interaction of an acridine orange ligand, [...] Read more.
Herein, we describe the synthesis of an aptadendrimer by covalent bioconjugation of a gallic acid–triethylene glycol (GATG) dendrimer with the G-quadruplex (G4) AT11 aptamer (a modified version of AS1411) at the surface. We evaluated the loading and interaction of an acridine orange ligand, termed C8, that acts as an anticancer drug and binder/stabilizer of the G4 structure of AT11. Dynamic light scattering experiments demonstrated that the aptadendrimer was approximately 3.1 nm in diameter. Both steady-state and time-resolved fluorescence anisotropy evidenced the interaction between the aptadendrimer and C8. Additionally, we demonstrated that the iodine atom of the C8 ligand acts as an effective intramolecular quencher in solution, while upon complexation with the aptadendrimer, it adopts a more extended conformation. Docking studies support this conclusion. Release experiments show a delivery of C8 after 4 h. The aptadendrimers tend to localize in the cytoplasm of various cell lines studied as demonstrated by confocal microscopy. The internalization of the aptadendrimers is not nucleolin-mediated or by passive diffusion, but via endocytosis. MTT studies with prostate cancer cells and non-malignant cells evidenced high cytotoxicity mainly due to the C8 ligand. The rapid internalization of the aptadendrimers and the fluorescence properties make them attractive for the development of potential nanocarriers. Full article
(This article belongs to the Special Issue Progress and Innovation on Nanosystems for Gene Therapy)
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Review

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25 pages, 2518 KiB  
Review
Delivery Systems for Mitochondrial Gene Therapy: A Review
by Rúben Faria, Prisca Boisguérin, Ângela Sousa and Diana Costa
Pharmaceutics 2023, 15(2), 572; https://doi.org/10.3390/pharmaceutics15020572 - 8 Feb 2023
Cited by 9 | Viewed by 4131
Abstract
Mitochondria are membrane-bound cellular organelles of high relevance responsible for the chemical energy production used in most of the biochemical reactions of cells. Mitochondria have their own genome, the mitochondrial DNA (mtDNA). Inherited solely from the mother, this genome is quite susceptible to [...] Read more.
Mitochondria are membrane-bound cellular organelles of high relevance responsible for the chemical energy production used in most of the biochemical reactions of cells. Mitochondria have their own genome, the mitochondrial DNA (mtDNA). Inherited solely from the mother, this genome is quite susceptible to mutations, mainly due to the absence of an effective repair system. Mutations in mtDNA are associated with endocrine, metabolic, neurodegenerative diseases, and even cancer. Currently, therapeutic approaches are based on the administration of a set of drugs to alleviate the symptoms of patients suffering from mitochondrial pathologies. Mitochondrial gene therapy emerges as a promising strategy as it deeply focuses on the cause of mitochondrial disorder. The development of suitable mtDNA-based delivery systems to target and transfect mammalian mitochondria represents an exciting field of research, leading to progress in the challenging task of restoring mitochondria’s normal function. This review gathers relevant knowledge on the composition, targeting performance, or release profile of such nanosystems, offering researchers valuable conceptual approaches to follow in their quest for the most suitable vectors to turn mitochondrial gene therapy clinically feasible. Future studies should consider the optimization of mitochondrial genes’ encapsulation, targeting ability, and transfection to mitochondria. Expectedly, this effort will bring bright results, contributing to important hallmarks in mitochondrial gene therapy. Full article
(This article belongs to the Special Issue Progress and Innovation on Nanosystems for Gene Therapy)
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23 pages, 1418 KiB  
Review
Recent Advance of Liposome Nanoparticles for Nucleic Acid Therapy
by Yongguang Gao, Xinhua Liu, Na Chen, Xiaochun Yang and Fang Tang
Pharmaceutics 2023, 15(1), 178; https://doi.org/10.3390/pharmaceutics15010178 - 4 Jan 2023
Cited by 28 | Viewed by 3912
Abstract
Gene therapy, as an emerging therapeutic approach, has shown remarkable advantages in the treatment of some major diseases. With the deepening of genomics research, people have gradually realized that the emergence and development of many diseases are related to genetic abnormalities. Therefore, nucleic [...] Read more.
Gene therapy, as an emerging therapeutic approach, has shown remarkable advantages in the treatment of some major diseases. With the deepening of genomics research, people have gradually realized that the emergence and development of many diseases are related to genetic abnormalities. Therefore, nucleic acid drugs are gradually becoming a new boon in the treatment of diseases (especially tumors and genetic diseases). It is conservatively estimated that the global market of nucleic acid drugs will exceed $20 billion by 2025. They are simple in design, mature in synthesis, and have good biocompatibility. However, the shortcomings of nucleic acid, such as poor stability, low bioavailability, and poor targeting, greatly limit the clinical application of nucleic acid. Liposome nanoparticles can wrap nucleic acid drugs in internal cavities, increase the stability of nucleic acid and prolong blood circulation time, thus improving the transfection efficiency. This review focuses on the recent advances and potential applications of liposome nanoparticles modified with nucleic acid drugs (DNA, RNA, and ASO) and different chemical molecules (peptides, polymers, dendrimers, fluorescent molecules, magnetic nanoparticles, and receptor targeting molecules). The ability of liposome nanoparticles to deliver nucleic acid drugs is also discussed in detail. We hope that this review will help researchers design safer and more efficient liposome nanoparticles, and accelerate the application of nucleic acid drugs in gene therapy. Full article
(This article belongs to the Special Issue Progress and Innovation on Nanosystems for Gene Therapy)
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