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

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 (O₂ ^•-) 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.