Image-guided photodynamic therapy (PDT) can realize highly precise and effective therapy due to the integration of imaging and therapy, and put forward high requirement for photosensitizers. However, the PDT modality...

fidelity diagnosis is of great importance for follow-up treatment. [1] However, traditional histological hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining cannot realize intraoperative pathological diagnosis, [2] because of their inherent complicated operation protocols with time-consuming, let alone in vivo tracking of PC (Figure 1A). Although immune-fluorescence (IF)-based technologies [3] have facilitated some aspects of histological evaluation, the deadly aggregation-caused quenching (ACQ) effects and poor photostability of most commercial dyes make the readout fluorescent signal to be with low signal/noise (S/N) and poor stability. [4] Moreover, the uncontrollable nonspecific attachment of IF dyes to biological tissues may interfere with the distinction between tumor (T) tissues and paratumor (PT) tissues (Figure 1A). As a consequence, it is of great urgency to develop an efficient and early clinical tool for real-time and high-specificity in situ diagnosing of PC.Recently, the vigorous and robust aggregation-induced emission luminogens (AIEgens) have expanded the database of fluorescent probes with targeting events through aggregation process, available for real-time and in situ imaging with excellent photostability, high-resolution, and long-term tracking ability. [5] However, the current AIEgens probes are still not ideal due to the Pancreatic cancer (PC) is one of the most devastating malignant tumors. However, fluorescence probes for early clinical diagnosis of PC often encounter difficulties in accuracy and penetrability. In this work, an enzymeactivated aggregation-induced-emission (AIE) probe, QM-HSP-CPP, for highcontrast fluorescence diagnosis of PC is developed by monitoring specific overexpressed enzyme Cathepsin E (CTSE). The probe is composed of an AIE fluorophore QM-COOH (QM = quinoline-malononitrile), CTSE-triggered hydrophobic peptide (HSP), and hydrophilic biocompatible cell penetrating peptide (CPP). The CPP unit can well-modulate the molecular dispersion properties, giving initial fluorescence-off state in the aqueous biosystem, thus endowing high signal-to-noise ratio, and finally overcoming the poor targeting selectivity of traditional AIE probes. CPP can ensure cell/tissue penetrating ability, thus allowing on-site monitoring of endogenous CTSE in PC cells, tissues, and living animal models. When the QM-HSP-CPP probe is specifically cleaved by CTSE, it can generate AIE signals in situ with high-specificity and long-term tracking ability, and successfully achieve intraoperative diagnosis of human PC sections, tracking PC in heterotopic nude mice models. The CTSE-enzyme-triggered AIEgens' liberation strategy improves accuracy and addresses the penetration problem simultaneously, which can expand the database of multitudinous biocompatible AIE-active probes, especially for establishing intraoperative pathological fluorescent diagnosis.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adma.202107444.

The current aggregation-induced emission luminogens (AIEgens) sometimes suffer from poor targeting selectivity due to undesirable aggregation in hydrophilic biosystem with “always-on” fluorescence or unspecific aggregation in lipophilic organelle with premature activated fluorescence. Herein, we report an unprecedented “amphiphilic AIEgen” sensor QM-SO3-ER based on the AIE building block of quinoline-malononitrile (QM). The introduced hydrophilic sulfonate group can well control the specific solubility in hydrophilic system with desirable initial “fluorescence-off” state. Moreover, the incorporated p-toluenesulfonamide group plays two roles: enhancing the lipophilic dispersity, and behaving as binding receptor to the ATP-sensitive potassium (KATP) on endoplasmic reticulum (ER) membrane to generate the docking assay confinement effect with targetable AIE signal. The amphiphilic AIEgen has for the first time well settled down the predicament of unexpected “always-on” fluorescence in aqueous system and untargetable aggregation signal in lipophilic organelle before binding to ER, thus successfully overcoming the bottleneck of AIEgen targetability.

High-fidelity imaging and long-term visualization of lysosomes are crucial for their function evaluation, related diseases detection and active drug screening. However, the commercial aggregation-caused quenching (ACQ) probes are not conducive...