Smart Sonoafterglow Nanobombs for High‐Contrast Imaging and Synergistic Gas‐Sonodynamic Therapy of Hypoxic Tumors

ABSTRACT Precise diagnosis and effective eradication of hypoxic tumors remain formidable challenges in cancer therapy. Here, we report a smart sonoafterglow nanobomb ( TCL NPs ) featuring a single US‐triggered dual‐activation mechanism for ONOO − ‐activated afterglow imaging and CO‐gas potentiated sonodynamic therapy (SDT). TCL NPs are engineered from a sonosensitizer ( TTQ ), an ONOO − ‐responsive chemiluminescent substrate ( CL─COOCH 3 ), and a ROS‐activated CO prodrug ( DHF ). Upon ultrasound irradiation, TTQ generates ROS that oxidize CL─COOCH 3 , triggering a bright near–infrared afterglow via chemiluminescence resonance energy transfer (CRET) for high‐contrast, real‐time tumor visualization. Simultaneously, the generated ROS induce CO release from DHF prodrug, which effectively alleviates tumor hypoxia and potentiates SDT efficacy. Due to this dual‐activation mechanism, TCL NPs achieve precise ONOO − ‐sensitive imaging, robust tumor suppression, and potent induction of immunogenic cell death in vivo. Overall, unlike prior approaches that address either tumor imaging or hypoxia modulation alone, this work establishes a versatile sonoafterglow nanobomb for oxygen‐independent, image‐guided, and synergistic tumor theranostics.