Versatile lysine-based bioreducible nanogel for chemical drug and nucleic acid therapeutics delivery

Most nano-sized drug delivery carriers are usually taken up by cells through the endocytosis pathway. During this process, the nanoparticles have trapped in acidic vesicles (e.g. the endosomes, endolysosomes, and lysosomes). To deliver the therapeutics to the target site, the nanoparticles must escape from the endosomes before reaching the lysosomes. Therefore, various endosomolytic agents have been investigated to overcome the loss of therapeutics in the lysosomes. In our previous study, epsilon poly-L-lysine (EPL) exhibited endosomolytic activity, unlike alpha poly-L-lysine (APL). However, EPL cannot load hydrophobic chemical drugs and has low gene delivery efficiency due to its lack of hydrophobic space, loose complexation, and rapid decomplexation properties. To address this issue, we designed reducible EPL nanogels (REPL-NGs) to develop versatile drug delivery carriers capable of endosome escape. REPL-NGs have hydrophobic and reducible disulfide bonds that endow hydrophobic space and tunable complexation and decomplexation for more effective drug encapsulation and release. REPL exists in the nanogel state in aqueous solutions because it has hydrophilic amines and hydrophobic disul-fide bonds on the surface and interior of the nanogel, respectively. To deliver nucleic acid therapeutics, cationic REPL-NG could be complexed with anionic plasmid DNA (pDNA) or messenger RNA (mRNA) through electrostatic interactions. The gene delivery efficiency of these complexes was higher than that of EPL/pDNA and EPL/mRNA complexes. In addition, hydrophobic drug (i.e., doxorubicin (DOX) were loaded into REPL-NGs (DOX@REPL-NG) by hydrophobic interaction, and it was administered to the HCT116-xenograft mouse model. The results showed that DOX@REPL-NG exhibited superior antitumor effects than free DOX-HCl. In conclusion, REPL-NG could be utilized as a versatile nano-sized drug delivery carrier for the delivery of various therapeutics such as chemical drugs and genes.