Abstract
Extensive efforts and numerous methodologies have been explored to develop safe and efficient gene carriers that are capable of overcoming multiple extra- and intracellular barriers during the transfection process. However, it is a great challenge to fabricate a gene carrier system containing multiple functional components. In this work, we propose a facile modular approach to design targeted multifunctional gene delivery systems, which are based on building blocks with pre-defined functions to tackle specific barriers. These building blocks can be rationally combined and self-assemble into an integrated gene delivery system via host-guest interactions. As a proof of concept, three adamantyl-terminated targeting guest modules, adamantyl terminated RGD peptide (Ad-RGD), folate and lactobionic acid terminated PEGs (FA-PEG-Ad and LA-PEG-Ad), were synthesized, characterized, and utilized for post-functionalizing of adamantyl decorated cationic PEI based supramolecular polyplexes (PEI-Ad4/PCD/DNA) through the free CD units of the poly(β-cyclodextran) (PCD) host module. These multifunctional targeting supramolecular polyplexes exhibited enhanced cellular uptake and excellent transfection activity in receptor-positive cells. By modulating the functional components of the supramolecular platform, we can customize the gene carriers for further research on different tissues or cells in vitro or in vivo.
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