Reductive-damage-induced intracellular maladaptation for cancer electronic interference therapy

The cellular adaptation of cancer cells is the major obstacle for oxidative-damage-related therapies. Here, we introduce a counterintuitive strategy to utilize cells’ antioxidant defenses by using reductive damage to induce cellular maladaptation. By constructing a near infrared (NIR)-triggered endoplasmic reticulum (ER)-targeting electron donor, photogenerated electrons can destroy the oxidative microenvironment of ER in a reductive way, which realizes abnormal activation of the antioxidant defenses, aborts the protein folding process, and induces apoptosis to cancer cells. Notably, we observe for the first time the reductive damage process of electrons to protein disulfide bonds via transient absorption spectroscopy. In vitro and in vivo results show excess upregulated transcription factor Nrf2, elevated reductive equivalents, and efficient treatment effect. Our work underscores the utility of reductive damage by harnessing, rather than antagonizing, the intrinsic antioxidant defenses of cancer cells. This unique electronic interference therapy may have broad indications for other intractable diseases.