ε-Poly(l-lysine)-based bioreducible nanogels for mitochondria-targeted delivery and release: Hydrophobicity-tuned nucleus-to-mitochondria organelle-targeting switch and slow disulfide cleavage.

Hydrophobicity modulates both the nucleus-to-mitochondria targeting switch and slow disulfide cleavage, resulting in mitochondria-targeted delivery of DOX@REPL-NG and release of DOX from DOX@REPL-NG. [Display omitted] • A new nanogel delivers and releases hydrophobic payloads to mitochondria targets. • Hydrophobicity modulates both the switching of organelle targeting and slow disulfide cleavage. • Hydrophobic lysines preferentially select mitochondria. • Hydrophobic neighbors cause glutathione to slowly cleave the disulfide for slow drug release. Despite the significance of organelle-targeted delivery and the subsequent release of therapeutics, the therapeutic outcome of this technology is limited due to undesired organelle targeting and unwanted cytosolic drug release. In this study, an ε-poly(l -lysine) (EPL)-based bioreducible nanogel (REPL-NG) was designed to deliver and release hydrophobic payloads to mitochondria targets, and the NG was synthesized via a sequential thiolation and oxidation reaction. REPL-NG contains a hydrophilic NG surface, which provides colloidal stability in aqueous environments due to the ionizable amine in lysine. Hydrophobic chemicals were encapsulated as a result of the multiple disulfide-mediated and crosslinked inner compartments. The capability of the ionizable amines to buffer protons helped the NG escape endolysosomes. The neighboring hydrophobic lysine preferentially drove the NG into mitochondria rather than the nucleus, and the neighboring hydrophobic disulfide bonds were slowly cleaved by the intracellularly reduced glutathione (GSH) in mitochondria. In an HCT116 xenograft tumor-bearing mouse model, doxorubicin (DOX)-loaded REPL-NG (DOX@REPL-NG) resulted in better blood circulation, better tumor accumulation and retention, and ultimately more effective inhibition of tumor growth than free drugs. In conclusion, hydrophobicity could modulate both the nucleus-to-mitochondria targeting switch and slow disulfide cleavage, resulting in mitochondria-targeted delivery of DOX@REPL-NG and release of DOX from DOX@REPL-NG. [ABSTRACT FROM AUTHOR]