Combination therapy, especially photodynamic/photothermal therapy (PDT/PTT), has shown promising applications in cancer therapy. However, sequential irradiation by two different laser sources and even the utilization of single high-power laser to induce either combined PDT/PTT or individual PTT will be subjected to prolonged treatment time, complicated treatment process, and potential skin burns. Thus, low power single laser activatable combined PDT/PTT is still a formidable challenge. Herein, we propose an effective strategy to achieve synergistic cancer phototherapy under low power single laser irradiation for short duration. By taking advantage of dual plasmonic PTT nanoagents (AuNRs/MoS 2 ), a significant increase in temperature up to 60 °C with an overall photothermal conversion efficiency (PCE) of 68.8% was achieved within 5 min under very low power (0.2 W/cm 2 ) NIR laser irradiation. The enhanced PCE and PTT performance is attributed to the synergistic plasmonic PTT effect (PPTT) of dual plasmonic nanoagents, promoting simultaneous release (85%) of electrostatically bonded indocyanine green (ICG) to induce PDT effects, offering simultaneous PDT/synergistic PPTT. Both in vitro and in vivo investigations reveal complete cell/tumor eradication, implying that simultaneous PDT/synergistic PPTT effects induced by AuNRs/MoS 2 − ICG are much superior over individual PDT or synergistic PPTT. Notably, synergistic PPTT induced by dual plasmonic nanoagents also demonstrates higher in vivo antitumor efficacy than either individual PDT or PTT agents. Taken together, under single laser activation with low power density, the proposed strategy of simultaneous PDT/synergistic PPTT effectively reduces the treatment time, achieves high therapeutic index, and offers safe treatment option, which may serve as a platform to develop safer and clinically translatable approaches for accelerating cancer therapeutics.

Stimuli-responsive smart photosensitizer (PS) nanoassemblies that allowenhanced delivery and controlled release of PSs are promising for imaging-guided photodynamic therapy(PDT) of tumors.However,the lack of high-sensitivity and spatial-resolution signals and fast washout of released PSs from tumor tissues have impeded PDT efficacy in vivo.Herein, we report tumor targeting,r edox-responsive magnetic and fluorogenic PS nanoassemblies (NP-RGD)s ynthesized via self-assembly of acRGD-and disulfide-containing fluorogenic and paramagnetic small molecule (1-RGD)f or fluorescence/ magnetic resonance bimodal imaging-guided tumor PDT. NP-RGD show high r 1 relaxivity but quenched fluorescence and PDT activity;d isulfide reduction by glutathione (GSH) promotes efficient disassembly into as mall-molecule probe (2-RGD)a nd an organic PS (PPa-SH), whichc ould further bind with intracellular albumin, allowing prolonged retention and cascade activation of fluorescence and PDT to ablate tumors.

Activatable chemiluminescent probes that show enhanced chemiluminescence upon interaction with a molecular target of interest have offered promising tools for sensing and bioimaging in terms of low background, high sensitivity, and improved penetration depth in biological tissues. Here, we reported a γ-glutamyl transpeptidase (GGT) activatable chemiluminescent probe for real-time detection of GGT activity in vitro and in living mice. The probe was designed by caging an electron-withdrawing acrylic group-substituted Schaap’s phenoxy-dioxetane with a GGT-recognitive substrate (γ-Glu) and a self-immolative linker (p-aminobenzyl alcohol), which was initially chemiluminescence off. Upon interaction with GGT, strong chemiluminescence with a more than 800-fold turn-on ratio could be achieved in aqueous solution, allowing to specifically detect GGT activity with ultrahigh signal-to-background ratio and sensitivity in vitro and in live cells. We demonstrated that the probe was reliable to quantify the GGT in serum, permitting to accurately report the elevated levels of GGT in lipopolysaccharide-treated mouse serum. Moreover, through real-time chemiluminescence imaging of GGT activity, the designed probe was feasible to detect GGT-positive tumors in living mice after intravenous systemic administration. This study demonstrates the high potential of GGT-activatable chemiluminescent probe for serum assays and molecular imaging, which might find wide applications in diagnosis of GGT-related diseases.

γ-Glutamyl transpeptidase (GGT) is a cell-membrane-bound enzyme that is involved in various physiological and pathological processes and is regarded as a potential biomarker for many malignant tumors, precise detection of which is useful for early cancer diagnosis. Herein, a new GGT-activatable near-infrared (NIR) fluorescence imaging probe (GANP) by linking of a GGT-recognitive substrate γ-glutamate (γ-Glu) and a NIR merocyanine fluorophore (mCy-Cl) with a self-immolative linker p-aminobenzyl alcohol (PABA) is reported. GANP was stable under physiological conditions, but could be efficiently activated by GGT to generate ≈100-fold enhanced fluorescence, enabling high sensitivity (detection limit of ≈3.6 mU L ) and specificity for the real-time imaging of GGT activity as well as rapid evaluation of the inhibition efficacy of GGT inhibitors in living tumor cells. Notably, the deep tissue penetration ability of NIR fluorescence could further allow GANP to image GGT in frozen tumor tissue slices with large penetration depth (>100 μm) and in xenograft tumors in living mice. This GGT activatable NIR fluorescence imaging probe could facilitate the study and diagnosis of other GGT-correlated diseases in vivo.

Temporal control of delivery and release of drugs in tumors are important in improving therapeutic outcomes to patients. Here, we report a sequential stimuli-triggered in situ self-assembly and disassembly strategy to direct delivery and release of theranostic drugs in vivo. Using cisplatin as a model anticancer drug, we design a stimuli-responsive small-molecule cisplatin prodrug (P-CyPt), which undergoes extracellular alkaline phosphatase-triggered in situ self-assembly and succeeding intracellular glutathione-triggered disassembly process, allowing to enhance accumulation and elicit burst release of cisplatin in tumor cells. Compared with cisplatin, P-CyPt greatly improves antitumor efficacy while mitigates off-target toxicity in mice with subcutaneous HeLa tumors and orthotopic HepG2 liver tumors after systemic administration. Moreover, P-CyPt also produces activated near-infrared fluorescence (at 710 nm) and dual photoacoustic imaging signals (at 700 and 750 nm), permitting high sensitivity and spatial-resolution delineation of tumor foci and real-time monitoring of drug delivery and release in vivo. This strategy leverages the advantages offered by in situ self-assembly with those of intracellular disassembly, which may act as a general platform for the design of prodrugs capable of improving drug delivery for cancer theranostics.