“Dual‐Key”‐Controlled Activatable Semiconducting Polymer Nanoprobe for Highly Precision Phototheranostics Under NIR‐II Light Excitation

The development of activatable optical probes has proved to be a promising approach to improve the accuracy of phototheranostics. However, most such probes are usually responsive to single pathological factor and visible-near-infrared-I light upon activation, which restricts the theranostic specificity and tissue penetration depth, respectively. Herein, we develop a nitric oxide (NO) and acidity dual-stimuli responsive semiconducting polymer nanoprobe for activatable near-infrared-II (NIR-II) photoacoustic imaging (PAI) and photothermal therapy (PTT). Specifically, a weak electron acceptor (benzo[c][1,2,5]thiadiazole-5,6-diamine, BT2NH₂) has been conjugated with diketopyrrolopyrrole to construct the pathological factor-sensitive molecular probe. Upon the coactivation of NO and acidity, the BT2NH₂ is oxidized to generate a strong electron acceptor (5H-[1,2,3]triazolo[4,5-f]-2,1,3-benzothiadiazole, BT3N), leading to the absorption enhancement in the NIR-II region. In vitro and in vivo studies indicate the successful activation of the probe toward activated macrophages, various cancer cells, drug-induced liver injury, and breast cancer to output enhanced NIR-II photoacoustic and photothermal signals, permitting highly specific PAI and PTT with reduced background interference and minimal therapeutic side effects. By virtue of the improved specificity and superior penetration depth, the dual-stimuli responsive NIR-II probe has broad prospects for precise visualization and intervention toward NO and acid-associated pathological and physiological events from deep tissues.