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α‐Mannosyl‐Functionalized Cationic Nanohydrogel Particles for Targeted Gene Knockdown in Immunosuppressive Macrophages
Author(s) -
Leber Nadine,
Kaps Leonard,
Yang Aiting,
Aslam Misbah,
Giardino Mariacristina,
Klefenz Adrian,
Choteschovsky Niklas,
Rosigkeit Sebastian,
Mostafa Asmaa,
Nuhn Lutz,
Schuppan Detlef,
Zentel Rudolf
Publication year - 2019
Publication title -
macromolecular bioscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.924
H-Index - 105
eISSN - 1616-5195
pISSN - 1616-5187
DOI - 10.1002/mabi.201900162
Subject(s) - mannose receptor , gene knockdown , chemistry , gene delivery , small interfering rna , in vitro , biophysics , microbiology and biotechnology , macrophage , genetic enhancement , biochemistry , transfection , biology , gene
Immunosuppressive M2 macrophages govern the immunophathogenic micromilieu in many severe diseases including cancer or fibrosis, thus, their re‐polarization through RNA interference is a promising concept to support combinatorial therapies. For targeted siRNA delivery, however, safe and stable carriers are required that manage cell specific transport to M2 macrophages. Here, siRNA‐loaded cationic nanogels are reported with α‐mannosyl decorated surfaces that target and modify M2 macrophages selectively. Via amphiphilic precursor block copolymers bearing one single α‐mannosyl moiety at their chain end mannosylated cationic nanohydrogel particles (ManNP) were obtained of 20 nm diameter determined by dynamic light scattering and cryogenic electron transmission microscopy. α‐Mannosyl surface modification is confirmed by agglutination with concanavalin A. SiRNA‐loaded ManNP preferentially targets the overexpressed mannose receptor CD206 on M2 macrophages, as shown by in vitro cell uptake studies in M2 polarized primary macrophages. This specificity is confirmed, since ManNP uptake could be reduced by blocking of CD206 with mannan. Effective ManNP‐guided siRNA delivery is confirmed by sequence‐specific gene knockdown of CSF‐1R in M2‐type macrophages exclusively, while the expression levels in M1‐polarized macrophages is not affected. In conclusion, α‐mannosyl‐functionalized ManNPs are promising universal siRNA carriers for targeted immunomodulatory treatment of immunosuppressive macrophages.