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11 pages, 3076 KiB

Open AccessArticle

Polymeric Micelles with pH-Responsive Cross-Linked Core Enhance In Vivo mRNA Delivery

by Wenqian Yang, Pengwen Chen, Eger Boonstra, Taehun Hong and Horacio Cabral

Pharmaceutics 2022, 14(6), 1205; https://doi.org/10.3390/pharmaceutics14061205 - 06 Jun 2022

Cited by 9 | Viewed by 2764

Abstract

Messenger RNA (mRNA) is emerging as a promising therapeutic modality for a variety of diseases. Because of the fragility and limited intracellular access of mRNA, the development of delivery technologies is essential for promoting the applicability of mRNA-based treatments. Among effective nanocarriers, polymeric micelles loading mRNA by polyion complex (PIC) formation with block catiomers have the potential to meet the delivery needs. Since PICs are relatively unstable in in vivo settings, herein, we constructed mRNA-loaded micelles having pH-responsive cross-linked cores by complexing mRNA with cis-aconitic anhydride-modified poly(ethylene glycol)-poly(l-lysine) (PEG-pLL(CAA)) block copolymers. The micelles were stable at physiological pH (pH 7.4) but achieved the complete release of the mRNA at endosomal pH (pH 5.5–4.5). The cross-linking also enhanced the stability of the micelles against disassembly from polyanions and protected the loaded mRNA from degradation by nucleases. Thus, the cross-linked micelles increased the delivery of mRNA to cancer cells, promoting protein expression both in vitro and in vivo. Our results highlight the potential of PEG-pLL(CAA)-based micelles for mRNA delivery. Full article

(This article belongs to the Special Issue Messenger RNA Therapeutics)

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15 pages, 3117 KiB

Open AccessArticle

Homing of mRNA-Modified Endothelial Progenitor Cells to Inflamed Endothelium

by Denis Canjuga, Heidrun Steinle, Jana Mayer, Ann-Kristin Uhde, Gerd Klein, Hans Peter Wendel, Christian Schlensak and Meltem Avci-Adali

Pharmaceutics 2022, 14(6), 1194; https://doi.org/10.3390/pharmaceutics14061194 - 02 Jun 2022

Viewed by 1698

Abstract

Endothelial progenitor cells (EPCs) are one of the most important stem cells for the neovascularization of tissues damaged by ischemic diseases such as myocardial infarction, ischemic stroke, or critical limb ischemia. However, their low homing efficiency in the treatment of ischemic tissues limits their potential clinical applications. The use of synthetic messenger RNA (mRNA) for cell engineering represents a novel and promising technology for the modulation of cell behavior and tissue regeneration. To improve the therapeutic potential of EPCs, in this study, murine EPCs were engineered with synthetic mRNAs encoding C-X-C chemokine receptor 4 (CXCR4) and P-selectin glycoprotein ligand 1 (PSGL-1) to increase the homing and migration efficiency of EPCs to inflamed endothelium. Flow cytometric measurements revealed that the transfection of EPCs with CXCR4 and PSGL-1 mRNA resulted in increased expressions of CXCR4 and PSGL-1 on the cell surface compared with the unmodified EPCs. The transfection of EPCs with mRNAs did not affect cell viability. CXCR4-mRNA-modified EPCs showed significantly higher migration potential than unmodified cells in a chemotactic migration assay. The binding strength of the EPCs to inflamed endothelium was determined with single-cell atomic force microscopy (AFM). This showed that the mRNA-modified EPCs required a three-fold higher detachment force to be released from the TNF-α-activated endothelium than unmodified EPCs. Furthermore, in a dynamic flow model, significantly increased binding of the mRNA-modified EPCs to inflamed endothelium was detected. This study showed that the engineering of EPCs with homing factors encoding synthetic mRNAs increases the homing and migration potentials of these stem cells to inflamed endothelium. Thus, this strategy represents a promising strategy to increase the therapeutic potential of EPCs for the treatment of ischemic tissues. Full article

(This article belongs to the Special Issue Messenger RNA Therapeutics)

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33 pages, 23040 KiB

Open AccessEditor’s ChoiceReview

The Potential of Nanomedicine to Unlock the Limitless Applications of mRNA

by Laura Taina-González and María de la Fuente

Pharmaceutics 2022, 14(2), 460; https://doi.org/10.3390/pharmaceutics14020460 - 21 Feb 2022

Cited by 11 | Viewed by 5976

Abstract

The year 2020 was a turning point in the way society perceives science. Messenger RNA (mRNA) technology finally showed and shared its potential, starting a new era in medicine. However, there is no doubt that commercialization of these vaccines would not have been possible without nanotechnology, which has finally answered the long-term question of how to deliver mRNA in vivo. The aim of this review is to showcase the importance of this scientific milestone for the development of additional mRNA therapeutics. Firstly, we provide a full description of the marketed vaccine formulations and disclose LNPs’ pharmaceutical properties, including composition, structure, and manufacturing considerations Additionally, we review different types of lipid-based delivery technologies currently in preclinical and clinical development, namely lipoplexes and cationic nanoemulsions. Finally, we highlight the most promising clinical applications of mRNA in different fields such as vaccinology, immuno-oncology, gene therapy for rare genetic diseases and gene editing using CRISPR Cas9. Full article

(This article belongs to the Special Issue Messenger RNA Therapeutics)

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