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Saarland University

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J. Control. Release, 2023 Jan;353:915-929 | https://doi.org/10.1016/j.jconrel.2022.12.018 Proteoid biodynamers for safe mRNA transfection via pH-responsive nanorods enabling endosomal escape

Sangeun Lee ^a,b, Sarah Nasr ^a,b,c, Sari Rasheed ^a,d, Yun Liu ^a, Olga Hartwig ^a,b, Cansu Kaya ^a,b, Annette Boese ^a, Marcus Koch^e, Jennifer Herrmann ^a,d, Rolf Müller ^a,b,d,f, Brigitta Loretz ^a, Eric Buhler^g, Anna K.H. Hirsch ^a,b,f, Claus-Michael Lehr^a,b

^aHelmholtz Institute for Pharmaceutical Research Saarland (HIPS) – Helmholtz Centre for Infection Research (HZI), Campus E 8.1, 66123 Saarbrücken, Germany
^bDepartment of Pharmacy, Saarland University, 66123 Saarbrücken, Germany
^cDepartment of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Egypt
^dGerman Centre for Infection Research (DZIF), Braunschweig, Germany
^eINM – Leibniz Institute for New Materials, Campus D2 2, 66123 Saarbrücken, Germany
^fHelmholtz International Lab – Helmholtz Centre for Infection Research (HZI), Campus E 8.1, 66123 Saarbrücken, Germany
^gLaboratoire Matière et Systèmes Complexes (MSC), UMR CNRS 7057, Université Paris Cité, Bâtiment Condorcet, 75205 Paris Cedex 13, France

Corresponding authors: Sangeun Lee, Anna K.H. Hirsch, Claus-Michael Lehr

Abstract

The recent success of mRNA vaccines using lipid-based vectors highlights the importance of strategies for nucleotide delivery under the pandemic situation. Although current mRNA delivery is focused on lipid-based vectors, still they need to be optimized for increasing stability, targeting, and efficiency, and for reducing toxicity. In this regard, other vector systems featuring smart strategies such as pH-responsive degradability and endosomal escape ability hold the potential to overcome the current limitations. Here, we report pH-responsive polymeric nanorods made of amino acid-derivatives connected by dynamic covalent bonds called proteoid-biodynamers, as mRNA vectors. They show excellent biocompatibility due to the biodegradation, and outstanding transfection. The biodynamers of Lys, His, and Arg or monomer mixtures thereof were shown to form nanocomplexes with mRNA. They outperformed conventional transfection agents three times regarding transfection efficacy in three human cell lines, with 82-98% transfection in living cells. Also, we confirmed that the biodynamers disrupted the endosomes up to 10-fold more in number than the conventional vectors. We discuss here their outstanding performance with a thorough analysis of their nanorod structure changes in endosomal microenvironments.

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형식Research article
게재일2023년 01월 (BRIC 등록일 2023-02-24)
연구진국외 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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