Polyornithine-based polyplexes to boost effective gene silencing in CNS disorders

Conejos‐Sánchez, Inmaculada; Gallon, Elena; Niño-Pariente, Amaya; Smith, JA; Fuente, Alerie Guzman de la; Canio, Ludovica Di; Pluchino, ﻿Stefano; Franklin, R. J. M.; Vicent, Marı́a J.

doi:10.1039/c9nr06187h

Cited by 12 publications

(6 citation statements)

References 89 publications

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“…As for OPCs, transfection with three particles made of polyornithine-based complexes, with different sizes and ζ-potentials at 100 nM siRNA, resulted in a range of decrease between 35 and 39%. 64 In comparison, the 53.4% knockdown efficiency of the h(A2B3)-1 polymer in our study reached an exciting degree which allows for further in vivo applications. Together with the results of the GFP silencing study, this work demonstrates the great potential of the h(A2B3)-1 polymer to silence an exogenous gene (GFP) and an endogenous housekeeping gene (GAPDH), which exists in high amounts, in both easy-to-transfect HeLa cells and hard-totransfect primary neural cells.…”

Section: Gene Uptake and Silencing On Primary Neural Cellsmentioning

confidence: 54%

Nontoxic, Biodegradable Hyperbranched Poly(β-amino ester)s for Efficient siRNA Delivery and Gene Silencing

Ooi,

Huang,

Lau

et al. 2024

ACS Appl. Mater. Interfaces

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RNA interference (RNAi)-mediated gene silencing is a promising therapeutic approach to treat various diseases, but safe and efficient delivery remains a major challenge to its clinical application. Non-viral gene vectors, such as poly(β-amino esters) (pBAEs), have emerged as a potential candidate due to their biodegradability, low toxicity profile, ease of synthesis, and high gene transfection efficiency for both DNA and siRNA delivery. However, achieving significant gene silencing using pBAEs often requires a large amount of polymer carrier (with polymer/siRNA weight ratio >100) or high siRNA dose (>100 nM), which might potentially exacerbate toxicity concerns during delivery. To overcome these barriers, we designed and optimized a series of hyperbranched pBAEs capable of efficiently condensing siRNA and achieving excellent silencing efficiency at a lower polymer/siRNA weight ratio (w/w) and siRNA dose. Through modulation of monomer combinations and branching density, we identified the topperforming hyperbranched pBAEs, named as h(A2B3)-1, which possess good siRNA condensation ability, low cytotoxicity, and high cellular uptake efficiency. Compared with Lipofectamine 2000, h(A2B3)-1 achieved lower cytotoxicity and higher siRNA silencing efficiency in HeLa cells at a polymer/siRNA weight ratio of 30 and 30 nM siRNA dose. Notably, h(A2B3)-1 enhanced the gene uptake in primary neural cells and effectively silenced the target gene in hard-to-transfect primary cortical neurons and oligodendrocyte progenitor cells, with gene knockdown efficiencies of 34.8 and 53.4% respectively. By incorporating a bioreducible disulfide compartment into the polymer backbone, the cytocompatibility of the h(A2B3)-1 was greatly enhanced while maintaining their good transfection efficiency. Together, the low cytotoxicity and high siRNA transfection efficiency of hyperbranched h(A2B3)-1 in this study demonstrated their great potential as a non-viral gene vector for efficient siRNA delivery and RNAi-mediated gene silencing. This provides valuable insight into the future development of safe and efficient non-viral siRNA delivery systems as well as their translation into clinical applications.

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Section: Gene Uptake and Silencing On Primary Neural Cellsmentioning

confidence: 54%

Nontoxic, Biodegradable Hyperbranched Poly(β-amino ester)s for Efficient siRNA Delivery and Gene Silencing

Ooi,

Huang,

Lau

et al. 2024

ACS Appl. Mater. Interfaces

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“…Vicent et al synthesized a series of poly-L-ornithine (PLO)-based polymers and loaded anti-death receptor 6 (DR6) siRNAs. 341 These PNPs can escape from the endosome/lysosome and release siDR6 via a primary amine-mediated proton sponge effect, thereby downregulating DR6 expression. The silencing of DR6 promotes remyelination and axon regeneration, which is expected to treat CNS disease.…”

Section: Engineering Carriers Loaded With a Single Nucleic Acid Drug ...mentioning

confidence: 99%

Nucleic acid drug vectors for diagnosis and treatment of brain diseases

Lü

Shen

Yang

et al. 2023

Sig Transduct Target Ther

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Nucleic acid drugs have the advantages of rich target selection, simple in design, good and enduring effect. They have been demonstrated to have irreplaceable superiority in brain disease treatment, while vectors are a decisive factor in therapeutic efficacy. Strict physiological barriers, such as degradation and clearance in circulation, blood-brain barrier, cellular uptake, endosome/lysosome barriers, release, obstruct the delivery of nucleic acid drugs to the brain by the vectors. Nucleic acid drugs against a single target are inefficient in treating brain diseases of complex pathogenesis. Differences between individual patients lead to severe uncertainties in brain disease treatment with nucleic acid drugs. In this Review, we briefly summarize the classification of nucleic acid drugs. Next, we discuss physiological barriers during drug delivery and universal coping strategies and introduce the application methods of these universal strategies to nucleic acid drug vectors. Subsequently, we explore nucleic acid drug-based multidrug regimens for the combination treatment of brain diseases and the construction of the corresponding vectors. In the following, we address the feasibility of patient stratification and personalized therapy through diagnostic information from medical imaging and the manner of introducing contrast agents into vectors. Finally, we take a perspective on the future feasibility and remaining challenges of vector-based integrated diagnosis and gene therapy for brain diseases.

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“…The gel bundles formed are also very effective when coalescing to form drug deposits after injection [76]. Amino acids based as gene delivery systems, such as poly(ornithine) and poly(lysine), have demonstrated the ability to silence gene expression and gene transfection for the treatment of the central nervous system and cancer [77][78][79]. Hydrogel systems based on self-assembled peptides have also been developed in tissue engineering and regenerative medicine [80][81][82].…”

Section: Other Application Of Peptide-based Hydrogelsmentioning

confidence: 99%

Repair of Peripheral Nerve Injury Using Hydrogels Based on Self-Assembled Peptides

Zhang

et al. 2021

Gels

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Peripheral nerve injury often occurs in young adults and is characterized by complex regeneration mechanisms, poor prognosis, and slow recovery, which not only creates psychological obstacles for the patients but also causes a significant burden on society, making it a fundamental problem in clinical medicine. Various steps are needed to promote regeneration of the peripheral nerve. As a bioremediation material, self-assembled peptide (SAP) hydrogels have attracted international attention. They can not only be designed with different characteristics but also be applied in the repair of peripheral nerve injury by promoting cell proliferation or drug-loaded sustained release. SAP hydrogels are widely used in tissue engineering and have become the focus of research. They have extensive application prospects and are of great potential biological value. In this paper, the application of SAP hydrogel in peripheral nerve injury repair is reviewed, and the latest progress in peptide composites and fabrication techniques are discussed.

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Polyornithine-based polyplexes to boost effective gene silencing in CNS disorders

Abstract: Novel biodegradable and biocompatible polyornithine derivatives as non-viral vectors for siRNA exhibit effectively silence gene expression in primary neural cells.

Cited by 12 publications

References 89 publications

Nontoxic, Biodegradable Hyperbranched Poly(β-amino ester)s for Efficient siRNA Delivery and Gene Silencing

Nontoxic, Biodegradable Hyperbranched Poly(β-amino ester)s for Efficient siRNA Delivery and Gene Silencing

Nucleic acid drug vectors for diagnosis and treatment of brain diseases

Repair of Peripheral Nerve Injury Using Hydrogels Based on Self-Assembled Peptides

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