Figure 8. Schematic illustration of proposed LHH NP intracellular trafficking after systemic delivery.

i. The pegylated LHH NP shows extended blood circulation by evading the capture of reticuloendothelial system and extravsates into the interstitial space of the tumor due to the EPR effect. ii. The targeting ligand at the distal end of the PEG facilitates the cellular internalization of the NPs. iii, the NPs are entrapped in the endosomal compartment where the pH starts to drop. The lipase will strip the lipid membrane and the core is exposed to pH-activated cathepsin D enzyme. iv. The cationic lipid starts to destabilize the membrane structure due to the ion-exchange mechanism. Meanwhile, the pH-activated GALA peptide inserts into the compartment membrane and forms the barrel structure in the membrane to release endosome. v. After endosome escape, the degraded TH by cathepsin D demonstrates weakened binding affinity to the nucleic acids, leaving the anionic cargos to be easily released by the charge-based competitive displacement.