Drawing inspiration from reactive oxygen species capable of inducing lipid peroxidation, we explored chemical electron transfer (CET)-based self-activatable lipopolyplexes and lipid nanoparticles (LNPs) for producing singlet oxygen (¹O₂) in endosomes, disrupting endosomal membranes to enhance the escape of small interfering RNA (siRNA). Bis(2,4,6-trichlorophenyl) oxalate (TCPO) was adopted as CET donor, and gold nanoparticle or, alternatively, hemin served as acceptor. Donor and acceptor were simultaneously encapsulated inside lipopolyplex or LNP. The donor can be specifically self-activated by transferred chemical energy between TCPO and hydrogen peroxide that is overexpressed in tumor microenvironment. Enhanced endosomal escape was proved by using a fluorescent galectin-8 (Gal8)-mRuby reporter; ¹O₂ improved the recruitment of Gal8 by around 50-fold compared to the control group. Moreover, CET enabled a reduction of the required siRNA dose. Ionizable LNPs were optimized by testing different lipids and a four-armed oligoaminoamide or a mini U-shaped tetra-oleoyl tri-lysino succinoyl tetraethylene pentamine as ionizable oligocations. Superior gene silencing at low siRNA dose was demonstrated with three targets, green fluorescent protein as fluorescent marker, the oxidative stress induced nuclear factor erythroid 2-related factor 2 (Nrf2) as oxidative stress protein, or eglin 5 (EG5/KSP) as mitotic spindle motor protein. Nrf2 and EG5 gene knock-down resulted in tumor cell killing in culture. This research introduces a new perspective for facilitating endosomal escape of nucleic acids.