Sequential Unlocking of an RNS/ROS Storm via a Four‐Layer Logic‑Gated Ruthenium Nanocomposite for Hypoxia‐Tolerant Photodynamic Cancer Immunotherapy

ABSTRACT Tumor hypoxia, an immunosuppressive microenvironment, and the lack of spatiotemporally precise therapeutic activation collectively limit current cancer treatments. Here, we report a smart nanocomposite ( G&Ru@CuS ) that produces a localized reactive nitrogen species (RNS)/reactive oxygen species (ROS) storm controlled by four sequential logic gates. (i) Intracellular ROS degrade a thioketal‐crosslinked polymer gatekeeper, exposing the hollow CuS core. (ii) Acidic tumor pH (6.5–6.8) and high glutathione (GSH) trigger release of Cu 2+ , the NO donor S‐Nitrosoglutathione (GSNO), and a NO‐responsive mitochondria‐targeted prodrug photosensitizer Ru1 from the a degradable CuS scaffold. (iii) Cu 2+ catalyzes NO generation from GSNO. (iv) NO reacts with Ru1 to form Ru2 . Ru2 is an NO‐responsive prodrug photosensitizer that, upon activation, displays dual Type I/II photodynamic activity. It retains efficacy under hypoxia, rapidly depletes GSH, oxidizes NADH, and shows photocatalytic peroxidase activity, making it a powerful agent for triggering an RNS/ROS storm that drives tumor cell mitochondrial damage, necroptosis and ferroptosis, resulting in immunogenic cell death that promotes dendritic cell maturation and systemic antitumor immunity. In murine models, intravenous G&Ru@CuS achieves potent tumor inhibition with excellent immunotherapy and no systemic toxicity. This work is the first quadruple logic‐gated nanoplatform that overcomes hypoxia, enables spatiotemporal precision, and minimizes off‐target effects.