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. Korean researchers at College of Pharmacy, The Catholic University of Korea report an effective organelle (particularly, mitochondria)-targeted “delivery and release” nanogel. The study appears in the journal CHEMICAL ENGINEERING JOURNAL in January. 

For mitochondria-targeting, two key components such as lysines and disulfides in the nanogel were introduced. However, the lysines could deliver the nanogel to either mitochondria or the nucleus, the disulfides could be degraded in cytosol before reaching the mitochondria target. Work for more than four years by the researchers, led by Prof. Han Chang Kang, identified the critical roles of hydrophobicity, which regulates both nucleus-to-mitochondria organelle-targeting switch and slow disulfide cleavage, and realized an effective mitochondria-targeted “delivery and release” nanogel.

The researchers designed an ε-poly(L-lysine) (EPL)-based bioreducible nanogel (REPL-NG) for delivering hydrophobic payloads to mitochondria targets and then releasing the therapeutics from the nanogel in the mitochondria. 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. 

Prof. Kang said that “We showed for the first time the principle how cationic organelle-targeting moieties determine their delivery destination and how the degradation rates of disulfide bonds determine target organelles for drug release.” “Hydrophobic lysines make preferred mitochondria-to-nucleus nanogel delivery, and then slow cleavage of hydrophobic disulfides allows selective drug release from the nanogel in mitochondria but not cytosol. We also expect that our findings will provide a strategy to design an effective organelle-targeted drug and release system.”, Prof. Kang said.

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.(© 2022 Elsevier B.V. All rights reserved.)

[Reference] Cho H. et al., (2023) “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” Chemical Engineering Journal (doi.org/10.1016/j.cej.2022.141090)

[Main Author] Hana Cho (The Catholic University of Korea), Yeon Su Choi (The Catholic University of Korea), Da Gyeom Choung (The Catholic University of Korea), Han Chang Kang (The Catholic University of Korea)

* Contact email : Professor Han Chang Kang (hckang@catholic.ac.kr)