期刊
MACROMOLECULAR BIOSCIENCE
卷 19, 期 7, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/mabi.201900162
关键词
gene knock-down; M2 macrophages; mannose targeting; nanohydrogels; siRNA delivery
资金
- German Research Foundation (DFG) Collaborative Research Center [SFB 1066]
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 alpha-mannosyl decorated surfaces that target and modify M2 macrophages selectively. Via amphiphilic precursor block copolymers bearing one single alpha-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. alpha-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, alpha-mannosyl-functionalized ManNPs are promising universal siRNA carriers for targeted immunomodulatory treatment of immunosuppressive macrophages.
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