Maintaining the silence: reflections on long-term RNAi

Raemdonck, Koen; Vandenbroucke, Roosmarijn E.; Demeester, Joseph; Sanders, Niek N.; Smedt, Stefaan C. De

doi:10.1016/j.drudis.2008.06.008

Cited by 105 publications

(79 citation statements)

References 167 publications

(217 reference statements)

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“…This is thought to originate from Dicer recognition and cleavage which could improve their incorporation into RISC. Moreover, the introduction of chemical modifications to decrease their susceptibility for nuclease degradation could also have its implications on the persistence of the RNAi effect relative to unmodified duplexes [13]. Especially following a prolonged incubation in the (nuclease rich) intracellular environment, the use of chemically modified DsiRNAs could be an advantage over unmodified 21 mer siRNAs.…”

Section: Resultsmentioning

confidence: 99%

“…One of the limitations of non-viral carriers for synthetic siRNA delivery, especially when long-term treatment is advised, is the transient nature of the gene silencing effect as a result of cell division and intracellular siRNA degradation [13][14][15][16]. On the other hand, major concerns are raised with regard to adverse effects of siRNA therapeutics, such as unwanted immune activation [17], off-target silencing [18] and saturation of the RNAi machinery [19].…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, major concerns are raised with regard to adverse effects of siRNA therapeutics, such as unwanted immune activation [17], off-target silencing [18] and saturation of the RNAi machinery [19]. As these effects are concentration-dependent it is obvious that delivery of siRNA requires rigorous control over the intracellular siRNA concentrations [13,20]. As a consequence, delivery strategies that are able to control the amount of siRNA that is released in the cytoplasm as a function of time could be of interest to obtain a prolonged gene silencing and/or to minimize side-effects.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Prolonged gene silencing by combining siRNA nanogels and photochemical internalization

Raemdonck

Naeye

Høgset

et al. 2010

Journal of Controlled Release

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Small interfering RNAs (siRNAs) show potential for the treatment of a wide variety of pathologies with a known genetic origin through sequence-specific gene silencing. However, siRNAs do not have favorable drug-like properties and need to be packaged into nanoscopic carriers that are designed to guide the siRNA to the cytoplasm of the target cell. In this report biodegradable cationic dextran nanogels are used to deliver siRNA across the intracellular barriers. For the majority of non-viral siRNA carriers studied so far, endosomal confinement is identified as the most prominent hurdle, limiting the full gene silencing potential. Thus, there is a major interest in methods that are able to enhance endosomal escape of siRNA to improve its intracellular bioavailability. Photochemical internalization (PCI) is a method that employs amphiphilic photosensitizers to destabilize endosomal vesicles. We show that applying PCI at a later time-point post-transfection significantly prolonged the knockdown of the target protein only in case the siRNA was carried by nanogels and not when a liposomal carrier was used. Combining siRNA nanogels and PCI creates new possibilities to prolong gene silencing by using intracellular vesicles as depots for siRNA and applying PCI at the time when maintaining the RNAi effect becomes critical. Graphical abstractCombining siRNA nanogels and photochemical internalization (PCI) creates new possibilities to prolong gene silencing by using intracellular vesicles as depots and applying PCI at the time when maintaining the RNAi effect becomes critical.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Prolonged gene silencing by combining siRNA nanogels and photochemical internalization

Raemdonck

Naeye

Høgset

et al. 2010

Journal of Controlled Release

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“…Since synthetic siRNA can be designed to target nearly any human gene, RNAi has become the method of choice to suppress gene expression for therapeutic purposes. Over the last decade, several excellent reviews have been published on the concept of RNAi [1][2][3] and its clinical potential [4,5]. Different target tissues and modes of administration have already been evaluated for siRNA, but most successes to date have emerged from local delivery.…”

Section: Introductionmentioning

confidence: 99%

The Influence of Natural Pulmonary Surfactant on The Efficacy of siRNA-Loaded Dextran Nanogels

et al. 2013

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Aims: Topical administration of small interfering RNA (siRNA) nanocarriers is a promising approach in the treatment of pulmonary disorders. Pulmonary surfactant, covering the entire alveolar surface of mammalian lungs, will be one of the first interfaces that siRNA nanocarriers encounter upon inhalation therapy. Therefore, it is of outstanding importance to evaluate the impact of pulmonary surfactant on the performance of siRNA nanocarriers. Materials & Methods: The effect of natural lung-derived surfactants on the siRNA delivery capacity of dextran nanogels (DEX-NGs) is evaluated in vitro using flow cytometry and confocal microscopy.

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“…The application of siRNAs, designed to block the expression of disease-related proteins, has therefore emerged as a promising therapeutic strategy for the treatment of various diseases [1][2][3]. Pulmonary disorders, including chronic obstructive pulmonary disease (COPD) and lower respiratory infections, are currently amongst the top ten causes of death worldwide [4,5].…”

Section: Introductionmentioning

confidence: 99%

Hybrid pulmonary surfactant-coated nanogels mediate efficient in vivo delivery of siRNA to murine alveolar macrophages

Backer

Naessens

Koker

et al. 2015

Journal of Controlled Release

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The local delivery of small interfering RNA (siRNA) to the lungs may provide a therapeutic solution to a range of pulmonary disorders. Resident alveolar macrophages (rAM) in the bronchoalveolar lumen play a critical role in lung inflammatory responses and therefore constitute a particularly attractive target for siRNA therapeutics. However, achieving efficient gene silencing in the lung while avoiding pulmonary toxicity requires appropriate formulation of siRNA in functional nanocarriers. In this study, we evaluated pulmonary surfactant-coated dextran nanogels for the delivery of siRNA to rAM upon pharyngeal aspiration in BALB/c mice. Both the surfactant-coated and uncoated nanogels achieved high levels of siRNA uptake in rAM, yet only the surfactant-coated formulation could significantly reduce gene expression on the protein level. Surfactant-coated nanogels induced a profound downregulation of target mRNA levels, reaching 70% knockdown with ~1 mg kg -1 siRNA dose. In addition, only mild acute pro-inflammatory cytokine and chemokine responses were detected one day after nanoparticle aspiration, accompanied by a moderate neutrophil infiltration in the bronchoalveolar lumen. The latter could be substantially reduced by removal of excess surfactant from the formulation. Overall, our hybrid core-shell nanoparticles have demonstrated safe and effective siRNA delivery to rAM, providing a new therapeutic approach for treatment of inflammatory pathologies in the lung.

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Maintaining the silence: reflections on long-term RNAi

Cited by 105 publications

References 167 publications

Prolonged gene silencing by combining siRNA nanogels and photochemical internalization

Prolonged gene silencing by combining siRNA nanogels and photochemical internalization

The Influence of Natural Pulmonary Surfactant on The Efficacy of siRNA-Loaded Dextran Nanogels

Hybrid pulmonary surfactant-coated nanogels mediate efficient in vivo delivery of siRNA to murine alveolar macrophages

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