Proteoid biodynamers for safe mRNA transfection via pH-responsive nanorods enabling endosomal escape

Lee, Sangeun; Nasr, S. Seif El; Rasheed, Sari; Liu, Yun; Hartwig, Olga; Kaya, Cansu; Boese, Annette; Koch, Marcus; Herrmann, Jennifer; Müller, Rolf; Loretz, Brigitta; Hirsch, Anna K. H.; Lehr, Claus‐Michael

doi:10.1016/j.jconrel.2022.12.018

Cited by 11 publications

(13 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, polyplexes are often unstable in isotonic conditions . Here, the Lys side chains in the DPs were cross-linked using XL to improve the stability of DPs in physiological conditions . We evaluated the cross-linking effect on the D H of DPs, morphology, drug loading, and stability.…”

Section: Resultsmentioning

confidence: 99%

“…Lys-hydrazides and Lys-biodynamers were synthesized using the previously reported method 30 and characterized using 1 H NMR and FT-IR spectroscopy. For the successful synthesis of Lys-hydrazides, the proton peak at δ = 3.78 ppm was flattened in 1 H NMR (Figure S1A,B); 27 moreover, the absorption around 1228 cm −1 decreased in FT-IR, which was caused by the reaction and replacement of the methyl ester group on Lys-methyl ester with hydrazide.…”

Section: Synthesis and Characterization Of Lys-biodynamersmentioning

confidence: 99%

“…43 Here, the Lys side chains in the DPs were cross-linked using XL to improve the stability of DPs in physiological conditions. 30 We evaluated the cross-linking effect on the D H of DPs, morphology, drug loading, and stability. First, we varied the amount of XL against the mass of the biodynamer in the DPs (0, 10, 25, and 50 wt %) and measured the D H of DPs after cross-linking.…”

Section: Effect Of Cross-linking Onmentioning

confidence: 99%

“…Lysine is a basic amino acid with a positive charge under physiological conditions due to the protonation of the primary amine on its side chain . It was shown that the positively charged side chains of the amino acid hydrazides sped up biodynamer formation, gave them a nanorod structure, and contributed to compacting the negatively charged nucleotides …”

Section: Introductionmentioning

confidence: 99%

“…28 It was shown that the positively charged side chains of the amino acid hydrazides sped up biodynamer formation, gave them a nanorod structure, 29 and contributed to compacting the negatively charged nucleotides. 30 Here, we designed a siRNA delivery system based on cationic biodynamers under the hypothesis that the acidresponsive dynamic nature of the biodynamers is beneficial for siRNA release and endosomal escape in addition to excellent biocompatibility. In this study, we first established and optimized biodynamic nanocomplex (dynaplexes, DPs) formation between a model siRNA and Lys-biodynamers in terms of the size and polydispersity of DPs, stability, loading capacity, and the pH-responsive behavior of DPs.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

pH-Responsive Dynaplexes as Potent Apoptosis Inductors by Intracellular Delivery of Survivin siRNA

Liu,

Ashmawy,

Latta

et al. 2023

Biomacromolecules

Self Cite

View full text Add to dashboard Cite

Gene knockdown by siRNA offers an unrestricted choice of targets and specificity based on the principle of complementary Watson−Crick base pairing with mRNA. However, the negative charge, large molecular size, and susceptibility to enzymatic degradation of siRNA impede its successful transfection, hence limiting its potential for therapeutic use. The development of efficient and safe siRNA transfection agents is, therefore, critical for siRNA-based therapy. Herein, we developed a protein-based biodynamic polymer (biodynamer) that showed potential as a siRNA transfection vector, owing to its excellent biocompatibility, easy tunability, and dynamic polymerization under acidic environments. The positively charged biodynamers formed stable dynamic nanocomplexes (XL-DPs, hydrodynamic diameter of approximately 104 nm) with siRNA via electrostatic interactions and chemical cross-linking. As a proof of concept, the optimized XL-DPs were stable in physiological conditions with serum proteins and demonstrated significant pH-dependent size change and degradability, as well as siRNA release capability. The minimal cytotoxicity and excellent cellular uptake of XL-DPs effectively supported the intracellular delivery of siRNA. Our study demonstrated that the XL-DPs in survivin siRNA delivery enabled potent knockdown of survivin mRNA and induced notable apoptosis of carcinoma cells (2.2 times higher than a lipid-based transfection agent, Lipofectamine 2000). These findings suggested that our XL-DPs hold immense potential as a promising platform for siRNA delivery and can be considered strong candidates in the advancement of next-generation transfection agents.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Synthesis and Characterization Of Lys-biodynamersmentioning

confidence: 99%

Section: Effect Of Cross-linking Onmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

pH-Responsive Dynaplexes as Potent Apoptosis Inductors by Intracellular Delivery of Survivin siRNA

Liu,

Ashmawy,

Latta

et al. 2023

Biomacromolecules

Self Cite

View full text Add to dashboard Cite

show abstract

A Novel CRISPR/Cas9‐Encapsulated Biomimetic Manganese Sulfide Nanourchins for Targeted Magnetic Resonance Contrast Enhancement and Self‐Enhanced Chemodynamics‐Gene‐Immune Synergistic Tumor Therapy

Liu,

Mu,

Hou

et al. 2024

Adv Funct Materials

View full text Add to dashboard Cite

CRISPR/Cas9 gene editing systems are widely studied in cancer therapy, however, it is still challenging to improve the gene editing efficiency and enhance the anticancer efficacy. Herein, a novel self‐assembled manganese sulfide nanourchin with CRISPR/Cas9 and hybrid membrane encapsulation (MCRT) is developed to highlight the synergistic mechanism of hydrogen sulfide (H2S) and CRISPR/Cas9 in cancer therapy. The special structure and cationic surface of nanourchins facilitate the loading of CRISPR/Cas9 with the large size and the encapsulation of erythrocyte‐tumor cell hybrid membrane, endowing the nanoplatform with long circulation and precise tumor targeting. MCRT with pH‐response can effectively decompose into H2S and Mn2+, and release CRISPR/Cas9 in acidic tumor microenvironment. H2S can up‐regulate intracellular hydrogen peroxide level by inhibiting the activity of catalase, which enables self‐enhanced chemodynamic therapy (CDT) of Mn2+. In addition, H2S can synergize with the released CRISPR/Cas9, co‐downregulating the level of intracellular anti‐apoptotic protein survivin, achieving self‐enhanced gene therapy. Furthermore, systemic delivery of MCRT displays significantly tumor magnetic resonance imaging (MRI) contrast enhancement. Importantly, H2S‐enhanced CDT‐gene therapy simultaneously induces immunogenic cell death and triggered a robust anti‐tumor immune response. Thus, MCRT has a potential application for the targeted MRI and self‐enhanced CDT‐gene‐immune synergistic tumor therapy.

show abstract

Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery

Huang,

Deng,

Wang

et al. 2023

Advanced Materials

View full text Add to dashboard Cite

Messenger RNA (mRNA)‐based therapy has emerged as a powerful, safe, and rapidly scalable therapeutic approach that involves technologies for both mRNA itself and the delivery vehicle. Although there are some unique challenges for different applications of mRNA therapy, a common challenge for all mRNA therapeutics is the transport of mRNA into the target cell cytoplasm for sufficient protein expression. This review is focused on the behaviors at the cellular level of nanotechnology‐mediated mRNA delivery systems, which have not been comprehensively reviewed yet. First, the four main therapeutic applications of mRNA are introduced, including immunotherapy, protein replacement therapy, genome editing, and cellular reprogramming. Second, common types of mRNA cargos and mRNA delivery systems are summarized. Third, strategies to enhance mRNA delivery efficiency during the cellular trafficking process are highlighted, including accumulation to the cell, internalization into the cell, endosomal escape, release of mRNA from the nanocarrier, and translation of mRNA into protein. Finally, the challenges and opportunities for the development of nanotechnology‐mediated mRNA delivery systems are presented. This review can provide new insights into the future fabrication of mRNA nanocarriers with desirable cellular trafficking performance.

show abstract

Proteoid biodynamers for safe mRNA transfection via pH-responsive nanorods enabling endosomal escape

Cited by 11 publications

References 44 publications

pH-Responsive Dynaplexes as Potent Apoptosis Inductors by Intracellular Delivery of Survivin siRNA

pH-Responsive Dynaplexes as Potent Apoptosis Inductors by Intracellular Delivery of Survivin siRNA

A Novel CRISPR/Cas9‐Encapsulated Biomimetic Manganese Sulfide Nanourchins for Targeted Magnetic Resonance Contrast Enhancement and Self‐Enhanced Chemodynamics‐Gene‐Immune Synergistic Tumor Therapy

Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery

Contact Info

Product

Resources

About