Abstract
Endosomal escape remains a well-known bottleneck for successful small interfering RNA (siRNA) therapeutics. Here, a chemical electron transfer (CET)-based self-activatable lipopolyplex is explored for producing singlet oxygen (1O2) in endosomes, thereby enhancing siRNA delivery. The lipopolyplex simultaneously encapsulates bis(2,4,6-trichlorophenyl) oxalate (TCPO), gold nanoparticles (GNs), and siRNA. GNs are specifically self-activated by the transferred chemical energy between TCPO and hydrogen peroxide, which is enhanced in the tumor microenvironment. Enhanced endosomal membrane damage is verified using a cytosolic fluorescent galectin-8 (Gal8)-mRuby reporter; the oxidation of 1O2 facilitates the rupture of endosomes within 4 h, improving the recruitment of Gal8 to disrupted endosomes up to ∼50-fold. This research demonstrates that CET can facilitate the transfer of nucleic acids from endosomes to the cytosol and provides a starting point for further cytosolic delivery applications.
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