A NIR‐Gated Nanogenerator Enables Low‐Dose Nitric Oxide‐Potentiated Phototherapy

ABSTRACT Light‐activatable nitric oxide (NO) donors are promising for precision cancer therapy but are hindered by premature leakage and a reliance on high dosages that may lead to off‐target cytotoxicity. Herein, we report a near‐infrared (NIR)‐gated nanogenerator (Cy‐NO NPs) engineered for low‐dose, NO‐potentiated multi‐modal cancer phototherapy. By anchoring a thiol‐functionalized ortho‐trifluoromethyl‐nitroaromatic moiety onto a cyanine (IR825) scaffold, the design ensures negligible NO leakage under oxidative, reductive, and thermal stresses, thereby eliminating systemic toxicity. Upon 808 nm excitation, the excited‐state energy dissipation is balanced to drive four concurrent pathways: (i) a photoinduced intramolecular electron transfer (PIET) process triggering a nitro‐to‐nitrite rearrangement for NO release; (ii) Type I & II photodynamic effects; (iii) photothermal conversion; and (iv) NIR‐II fluorescence emission. The released NO reacts in situ with simultaneous superoxide (O 2 •− ) bursts to yield highly cytotoxic peroxynitrites (ONOO − ). This synergistic ROS/RNS surge targets mitochondria, inducing membrane depolarization and rapid ATP depletion to trigger apoptosis. Guided by NIR‐II fluorescence imaging, this multi‐modal therapy achieves efficient tumor ablation in vivo, validating a potent low‐dose strategy for integrating controlled gas release with phototherapy.