Design and Engineering of Hypoxia and Acidic pH Dual‐Stimuli‐Responsive Intelligent Fluorescent Nanoprobe for Precise Tumor Imaging

Abstract Stimulus‐responsive fluorescence imaging modality shows great promise for detection of tumor due to the advantages of high sensitivity, simplicity and noninvasiveness. However, some non‐cancer regions including nodules and inflammation may also exhibit a stimulus‐related characteristic, which cause the problem of nonspecific responsiveness and then cause “false positive” results for tumor recognition. Herein, hypoxia and acidic pH, two typical features strongly associated with tumor invasion, progression and metastasis in tumor microenvironment (TME), are chosen as dual stimuli to fabricate “dual lock‐and‐key” fluorescent nanoprobe for highly specific and precise imaging of tumor cells. Mesoporous silica coated gold nanorods (AuNR@mSiO 2 ) are employed as nanocarrier and nanoquencher to load the pH‐sensitive fluorescent reporter (Rho‐TP). Azobenzene (azo) which can be reduced to amines by the highly expressed azoreductase under hypoxic conditions, is elected as the effective gatekeeper for AuNR@mSiO 2 by forming complex with β‐cyclodextrin polymer via host‐guest interaction (azo/β‐CDP). By elaborately combining the hypoxia‐responsive gatekeeper and pH‐responsive fluorescent signal reporter into one nanoprobe, sensitive and specific imaging of tumor cells can be realized. The fabricated dual lock‐and‐key fluorescent nanoprobe successfully further apply in tumor‐bearing mice model, which indicate potential of early diagnosis and assessment of cancer treatment.