Delivery of mRNA to platelets using lipid nanoparticles

Novakowski, Stefanie K.; Jiang, Kailun; Prakash, Gyan; Kastrup, Christian J.

doi:10.1038/s41598-018-36910-2

Cited by 30 publications

(25 citation statements)

References 37 publications

(44 reference statements)

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“…To identify key parameters predicting efficient LNP-mRNA delivery, we performed a comparative image-based analysis on intracellular trafficking of six LNP with distinct chemical composition and efficiency in primary human adipocytes. Contrary to what is generally assumed 10,30 , our analysis revealed that delivery efficacy is not proportional to total cellular uptake. For some LNP-mRNA formulations, a large fraction accumulates in a small population of early endosomes that progressively become defective in acidification, cargo transport and, importantly, delivery (Fig.…”

Section: Discussioncontrasting

confidence: 99%

Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale

Paramasivam

Franke

Stöter

et al. 2020

Preprint

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Delivery of exogenous mRNA using lipid nanoparticles (LNP) is a promising strategy for therapeutics. However, a bottleneck remains the poor understanding of the endosomal parameters that correlate with endosomal escape vs. cytotoxicity. To address this problem, we compared the endosomal distribution of six LNP-mRNA formulations of diverse chemical composition and efficacy in primary human adipocytes. Quantitative multi-parametric microscopic analysis revealed that total LNP uptake is a poor predictor of delivery. Prolonged uptake impaired endosomal acidification causing mRNA accumulation in compartments defective in cargo transport and unproductive for delivery, indicating parameters of cytotoxicity. In contrast, early endocytic/recycling compartments have the highest probability for mRNA escape. By super-resolution microscopy we could resolve single fluorescently labelled mRNA within sub-endosomal compartments and capture events of mRNA escape from Transferrin-positive recycling tubules. Our results shed light into the mechanisms of endosomal escape and define quantitative parameters that can guide the development of mRNA formulations towards high efficacy and low cytotoxicity.

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Section: Discussioncontrasting

confidence: 99%

Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale

Paramasivam

Franke

Stöter

et al. 2020

Preprint

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“…DNA in the form of a circular plasmid or messenger RNA (mRNA), which are longer than RNAi molecules, can also be loaded into nanocarriers to effectively express a protein in a target cell. [73][74][75][76] Moffett et al and Smith et al each developed a nanocarrier that specifically targets the T cells of patients and delivers mRNA or a DNA plasmid into the T cells to transform them into chimeric antigen receptor (CAR) T cells in situ or ex vivo. [77,78] In this nanocarrier, mRNA or a DNA plasmid encoding the CAR is condensed by incubation with poly(beta-amino ester) (PBAE) 447 polymer and a polyglutamic acid-antibody recognizing cluster of differentiation 3 (CD3), a protein found on the surface of T cells.…”

Section: Nucleic Acids As Therapeutics Using Nanocarriersmentioning

confidence: 99%

Realizing Cancer Precision Medicine by Integrating Systems Biology and Nanomaterial Engineering

et al. 2020

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Many clinical trials for cancer precision medicine have yielded unsatisfactory results due to challenges such as drug resistance and low efficacy. Drug resistance is often caused by the complex compensatory regulation within the biomolecular network in a cancer cell. Recently, systems biological studies have modeled and simulated such complex networks to unravel the hidden mechanisms of drug resistance and identify promising new drug targets or combinatorial or sequential treatments for overcoming resistance to anticancer drugs. However, many of the identified targets or treatments present major difficulties for drug development and clinical application. Nanocarriers represent a path forward for developing therapies with these “undruggable” targets or those that require precise combinatorial or sequential application, for which conventional drug delivery mechanisms are unsuitable. Conversely, a challenge in nanomedicine has been low efficacy due to heterogeneity of cancers in patients. This problem can also be resolved through systems biological approaches by identifying personalized targets for individual patients or promoting the drug responses. Therefore, integration of systems biology and nanomaterial engineering will enable the clinical application of cancer precision medicine to overcome both drug resistance of conventional treatments and low efficacy of nanomedicine due to patient heterogeneity.

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“…Liposomes are promising carrier systems for the targeted administration of substances in biomedical applications. They are used to deliver drugs such as small interfering ribonucleic acids, to prevent NPs degradation and to target specific cell types [13][14][15]. Additionally, the directed combination of organic and inorganic particulate systems has several advantages.…”

Section: Introductionmentioning

confidence: 99%

Tackling Complex Analytical Tasks: An ISO/TS-Based Validation Approach for Hydrodynamic Chromatography Single Particle Inductively Coupled Plasma Mass Spectrometry

et al. 2020

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Nano-carrier systems such as liposomes have promising biomedical applications. Nevertheless, characterization of these complex samples is a challenging analytical task. In this study a coupled hydrodynamic chromatography-single particle-inductively coupled plasma mass spectrometry (HDC-spICP-MS) approach was validated based on the technical specification (TS) 19590:2017 of the international organization for standardization (ISO). The TS has been adapted to the hyphenated setup. The quality criteria (QC), e.g., linearity of the calibration, transport efficiency, were investigated. Furthermore, a cross calibration of the particle size was performed with values from dynamic light scattering (DLS) and transmission electron microscopy (TEM). Due to an additional Y-piece, an online-calibration routine was implemented. This approach allows the calibration of the ICP-MS during the dead time of the chromatography run, to reduce the required time and enhance the robustness of the results. The optimized method was tested with different gold nanoparticle (Au-NP) mixtures to investigate the characterization properties of HDC separations for samples with increasing complexity. Additionally, the technique was successfully applied to simultaneously determine both the hydrodynamic radius and the Au-NP content in liposomes. With the established hyphenated setup, it was possible to distinguish between different subpopulations with various NP loads and different hydrodynamic diameters inside the liposome carriers.

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Delivery of mRNA to platelets using lipid nanoparticles

Cited by 30 publications

References 37 publications

Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale

Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale

Realizing Cancer Precision Medicine by Integrating Systems Biology and Nanomaterial Engineering

Tackling Complex Analytical Tasks: An ISO/TS-Based Validation Approach for Hydrodynamic Chromatography Single Particle Inductively Coupled Plasma Mass Spectrometry

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