NIR-II Photocatalytic-Triggered Pyroptosis via Built-In Electric Field-Enhanced Reactive Oxygen Species Generation in Au–Cu ₂ O Nanodumbbells

Hypoxia-induced therapeutic resistance remains a major challenge for reactive oxygen species (ROS)-mediated pyroptotic cancer therapy. To overcome this limitation, we developed Au-Cu₂O nanodumbbells (NDs) with photoresponsive built-in electric fields (BIEFs) via heterointerface engineering. This design enables oxygen-independent photocatalytic therapy under second near-infrared (NIR-II, 1064 nm) laser activation. The primary BIEF suppresses rapid recombination of photoexcited electron-hole (e^--h⁺) pairs and promotes hot-electron transfer upon 1064 nm laser excitation. Meanwhile, a secondary photoinduced BIEF, arising from dynamic interfacial charge redistribution, further enhances directional charge separation and significantly improves catalytic activity. This dual modulation of electric fields enables sustained production of superoxide (·O₂^-) and hydroxyl radicals (·OH) via direct electron transfer and Cu⁺-mediated Fenton-like reactions, thereby maintaining ROS generation even under hypoxic conditions. The elevated ROS levels efficiently activate pyroptotic signaling pathways, leading to cell membrane rupture and pro-inflammatory immune responses in tumor cells. Combined with NIR-II photoacoustic (PA) imaging, this theranostic system enables spatiotemporally precise and hypoxia-tolerant cancer therapy with minimal off-target toxicity.