Biochemical reprogramming of active-targeting and redox responsive nanoparticles for enhancing selective internalization

Selective internalization is urgently needed in accelerating drug release. Herein, the synergistic DOX@PBA-COS/γ-PGA nanoparticles with GGT/SA activate-targeting and pH-H₂O₂ sensitivities were successively synthetized through the entanglement of chitosan oligosaccharide (COS) chains with phenylboronic acid (PBA) and poly (γ-glutamic acid) (γ-PGA). DOX@PBA-COS/γ-PGA was highly susceptible to gamma-glutamyl transpeptidase (GGT)-targeting than sialic acid (SA)-targeting in HepG2 cells. The selective internalization of DOX@PBA-COS/γ-PGA in the order of HepG2＞HeLa＞MCF-7, due to the clathrin-mediated endocytosis and microtubule polymerization/vesicular transport in HepG2 cells. The innovative strategies to augment selective internalization through the synergistic γ-PGA shielding and redox homeostasis interference provide enlightenment in the hepatocellular carcinoma therapy.