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Optical imaging is an indispensable tool for non-invasive visualization of biomolecules in living organisms, thereby offering a sensitive approach for disease diagnosis and image-guided disease treatment. Single-lock activatable optical probes (SOPs) that specifically switch on optical signals in the presence of biomarkers-of-interest have shown both higher detection sensitivity and imaging quality as compared to conventional "always-on" optical probes. However, such SOPs can still show "false-positive" results in disease diagnosis due to non-specific biomarker expression in healthy tissues. By contrast, multi-lock activatable optical probes (MOPs) that simultaneously detect multiple biomarkers-of-interest could improve detection specificity towards certain biomolecular events or pathological conditions. In this Review, we discuss the recent advancements of enzyme-responsive MOPs, with a focus on their biomedical applications. The higher detection specificity of MOPs could in turn enhance disease diagnosis accuracy and improve treatment efficacy in image-guided disease therapy with minimal toxicity in the surrounding healthy tissues. Finally, we discuss the current challenges and suggest future applications of MOPs. [ABSTRACT FROM AUTHOR]

Protease inhibitors can modulate intratumoral metabolic processes to reprogram the immunosuppressive tumor microenvironment (TME), which however suffer from the limited efficacy and off‐targeted side effects. We report smart nano‐proteolysis targeting chimeras (nano‐PROTACs) with phototherapeutic ablation and cancer‐specific protein degradation to reprogram the TME for photo‐metabolic cancer immunotherapy. This nano‐PROTAC has a semiconducting polymer backbone linked with a cyclooxygenase 1/2 (COX‐1/2)‐targeting PROTAC peptide (CPP) via a cathepsin B (CatB)‐cleavable segment. CPP can be activated by the tumor‐overexpressed CatB to induce the degradation of COX‐1/2 via the ubiquitin‐proteasome system. The persistent degradation of COX‐1/2 depletes their metabolite prostaglandin E2 which is responsible for activation of immune suppressor cells. Such a smart PROTAC strategy synergized with phototherapy specifically reprograms the immunosuppressive TME and reinvigorates antitumor immunity. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) play a role in both pro- and anti-tumor functions; and the targeted polarization from M2 to M1 TAMs has become an effective therapy option. Although detection of M1 TAMs is imperative to assess cancer immunotherapeutic efficacy, existing optical probes suffer from shallow tissue penetration depth and poor specificity toward M1 TAMs. Herein, we report a tandem-locked NIR chemiluminescent (CL) probe for specific detection of M1 TAMs. Through a combined molecular engineering approach via both atomic alternation and introduction of electron-withdrawing groups, near-infrared (NIR) chemiluminophores are screened out to possess record-long emission (over 800 nm), record-high CL quantum yield (2.7 % einstein/mol), and prolonged half-life (7.7 h). Based on an ideal chemiluminophore, the tandem-locked probe (DPD GN ) is developed to only activate CL signal in the presence of both tumour (γ-glutamyl transpeptidase) and M1 macrophage biomarkers (nitric oxide). Such a tandem-lock design ensures its high specificity towards M1 macrophages in the tumor microenvironment over those in normal tissues or peripheral blood. Thus, DPD GN permits noninvasive imaging and tracking of M1 TAM in the tumor of living mice during R837 treatment, showing a good correlation with ex vivo methods. This study not only reports a new molecular approach towards highly efficient chemiluminophores but also reveals the first tandem-locked CL probes for enhanced imaging specificity., (© 2024 Wiley-VCH GmbH.)

Chemotherapy-induced peripheral neuropathy (CIPN) has a high prevalence but is poorly managed for cancer patients due to the lack of reliable and sensitive diagnostic techniques. Molecular optical imaging can provide a noninvasive way for real-time monitoring of CIPN; However, this is not reported, likely due to the absence of optical probes capable of imaging deep into the spinal canal and possessing sufficient sensitivity for minimal dosage through local injection into the dorsal root ganglia. Herein, a near-infrared (NIR) chemiluminophore (MPBD) with a chemiluminescence quantum yield higher than other reported probes is synthesized and a NIR activatable chemiluminescent probe (CalCL) is developed for in vivo imaging of CIPN. CalCL is constructed by caging MPBD with calpain-cleavable peptide moiety while conjugating polyethylene glycol chain to endow water solubility. Due to the deep-tissue penetration of chemiluminescence and specific turn-on response of CalCL toward calpain (a hallmark of CIPN), it allows for sensitive detection of paclitaxel-mediated CIPN in living mice, which is unattainable by fluorescence imaging. This study thus not only develops a highly efficient chemiluminescent probe, but also presents the first optical imaging approach toward high-throughput screening of neurotoxic drugs., (© 2023 Wiley-VCH GmbH.)

NETosis, the peculiar type of neutrophil death, plays important roles in pro-tumorigenic functions and inhibits cancer immunotherapy. Non-invasive real-time imaging is thus imperative for prognosis of cancer immunotherapy yet remains challenging. Herein, we report a Tandem-locked NETosis Reporter 1 (TNR 1 ) that activates fluorescence signals only in the presence of both neutrophil elastase (NE) and cathepsin G (CTSG) for the specific imaging of NETosis. In the aspect of molecular design, the sequence of biomarker-specific tandem peptide blocks can largely affect the detection specificity towards NETosis. In live cell imaging, the tandem-locked design allows TNR 1 to differentiate NETosis from neutrophil activation, while single-locked reporters fail to do so. The near-infrared signals from activated TNR 1 in tumor from living mice were consistent with the intratumoral NETosis levels from histological results. Moreover, the near-infrared signals from activated TNR 1 negatively correlated with tumor inhibition effect after immunotherapy, thereby providing prognosis for cancer immunotherapy. Thus, our study not only demonstrates the first sensitive optical reporter for noninvasive monitoring of NETosis levels and evaluation of cancer immunotherapeutic efficacy in tumor-bearing living mice, but also proposes a generic approach for tandem-locked probe design., (© 2023 Wiley-VCH GmbH.)