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Residual micrometastases following standard therapies limit our ability to cure many cancers. This article demonstrates a new therapy and visualization platform that targets residual cancer micrometastases with enhanced sensitivity and selectivity based on “tumor-targeted activation.” This targeted activation feature not only provides a potent therapeutic arm that is effective against chemoresistant disease while minimizing side effects due to nonspecific toxicities but also enables micrometastasis imaging in common sites of disease recurrence to screen patients harboring residual tumor deposits. This approach offers promise for treating and monitoring drug-resistant micrometastases presently “invisible” to clinicians. Drug-resistant micrometastases that escape standard therapies often go undetected until the emergence of lethal recurrent disease. Here, we show that it is possible to treat microscopic tumors selectively using an activatable immunoconjugate. The immunoconjugate is composed of self-quenching, near-infrared chromophores loaded onto a cancer cell-targeting antibody. Chromophore phototoxicity and fluorescence are activated by lysosomal proteolysis, and light, after cancer cell internalization, enabling tumor-confined photocytotoxicity and resolution of individual micrometastases. This unique approach not only introduces a therapeutic strategy to help destroy residual drug-resistant cells but also provides a sensitive imaging method to monitor micrometastatic disease in common sites of recurrence. Using fluorescence microendoscopy to monitor immunoconjugate activation and micrometastatic disease, we demonstrate these concepts of “tumor-targeted, activatable photoimmunotherapy” in a mouse model of peritoneal carcinomatosis. By introducing targeted activation to enhance tumor selectively in complex anatomical sites, this study offers prospects for catching early recurrent micrometastases and for treating occult disease.

Molecular imaging is a non‐invasive imaging method that is widely used for visualization and detection of biological events at cellular or molecular levels. Stimuli‐responsive linkers that can be selectively cleaved by specific biomarkers at desired sites to release or activate imaging agents are appealing tools to improve the specificity, sensitivity, and efficacy of molecular imaging. This review summarizes the recent advances of stimuli‐responsive linkers and their application in molecular imaging, highlighting the potential of these linkers in the design of activatable molecular imaging probes. It is hoped that this review could inspire more research interests in the development of responsive linkers and associated imaging applications. Stimuli‐responsive linkers are appealing tools to improve the specificity, sensitivity, and efficacy of molecular imaging. In this review, the recent examples and progress toward the development of stimuli‐responsive linkers and their application in molecular imaging are systematically summarized, highlighting the potential of these linkers in the design of activatable molecular imaging probes.

Accurate detection of H2S is crucial to understanding the occurrence and development of H2S-related diseases. However, the accurate and sensitive detection of H2S in vivo still faces great challenges due to the characteristics of H2S diffusion and short half-life. Herein, we report a H2S-activatable ratiometric near-infrared (NIR) fluorescence liposome nanoprobe HS-CG by the thin-film hydration method. HS-CG shows “always on” fluorescence signal at 816 nm and low fluorescence signal at 728 nm; the NIR fluorescence ratio between 728 and 816 nm (F728/F816) is low. Upon reaction with H2S, the fluorescence at 728 nm could be more rapidly turned on due to strong electrostatic interaction between enriched HS− and positively charged 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine (DPPC) doped in the liposome nanoprobe HS-CG, resulting in a large enhancement of F728/F816, which allows for sensitive visualization of the tumor H2S levels in vivo. This study demonstrates that this strategy of electrostatic adsorption between HS− and positively charged molecules provides a new way to enhance the reaction rate of the probe and H2S, thus serving as an effective platform for improving the sensitivity of imaging.

Radioimmunotherapy (RIT) is an advanced physical therapy used to kill primary cancer cells and inhibit the growth of distant metastatic cancer cells. However, challenges remain because RIT generally has low efficacy and serious side effects, and its effects are difficult to monitor in vivo. This work reports that Au/Ag nanorods (NRs) enhance the effectiveness of RIT against cancer while allowing the therapeutic response to be monitored using activatable photoacoustic (PA) imaging in the second near‐infrared region (NIR‐II, 1000–1700 nm). The Au/Ag NRs can be etched using high‐energy X‐ray to release silver ions (Ag+), which promotes dendritic cell (DC) maturation, enhances T‐cell activation and infiltration, and effectively inhibits primary and distant metastatic tumor growth. The survival time of metastatic tumor‐bearing mice treated with Au/Ag NR‐enhanced RIT is 39 days compared with 23 days in the PBS control group. Furthermore, the surface plasmon absorption intensity at 1040 nm increases fourfold after Ag+ are released from the Au/Ag NRs, allowing X‐ray activatable NIR‐II PA imaging to monitor the RIT response with a high signal‐to‐background ratio of 24.4. Au/Ag NR‐based RIT has minimal side effects and shows great promise for precise cancer RIT. This work reports X‐ray activatable Au/Ag core/shell nanorods (NRs) for tumor radioimmunotherapy (RIT) enhancement while achieving second near‐infrared region (NIR‐II) photoacoustic (PA) imaging to monitor the therapeutic response.

Tumor microenvironment (TME)‐triggered phototheranostic platform offers a feasible strategy to improve cancer diagnosis accuracy and minimize treatment side effects. Developing a stable and biocompatible molecular phototheranostic platform for TME‐activated second near‐infrared (NIR‐II) fluorescence imaging‐guided multimodal cascade therapy is a promising strategy for creating desirable anticancer agents. Herein, a new NIR‐II fluorescence imaging‐guided activatable molecular phototheranostic platform (IR‐FEP‐RGD‐S‐S‐S‐Fc) is presented for actively targeted tumor imaging and hydrogen sulfide (H2S) gas‐enhanced chemodynamic‐hypothermal photothermal combined therapy (CDT/HPTT). It is revealed for the first time that the coupling distance between IR‐FE and ferrocene is proportional to the photoinduced electron transfer (PET), and the aqueous environment is favorable for PET generation. The part of Cyclic‐RGDfK (cRGDfk) peptides can target the tumor and benefit the endocytosis of nanoparticles. The high‐concentration glutathione (GSH) in the TME will separate the fluorescence molecule and ferrocene by the GSH‐sensitive trisulfide bond, realizing light‐up NIR‐II fluorescence imaging and a cascade of trimodal synergistic CDT/HPTT/gas therapy (GT). In addition, the accumulation of hydroxyl radicals (•OH) and down‐regulation of glutathione peroxidase 4 (GPX4) can produce excessive harmful lipid hydroperoxides, ultimately leading to ferroptosis. Trisulfide bond‐mediated molecular phototheranostic platform for “activatable” NIR‐II imaging‐guided enhanced gas‐chemo‐hypothermal photothermal therapy. A new phototheranostic platform is developed, utilizing cyclic‐RGDfk (cRGDfk) peptide for active tumor cell targeting and achieving glutathione (GSH)‐rich tumor environment photoinduced electron transfer (PET) blockade for fluorescence‐specific illumination and therapy.

Aptamers have emerged as promising molecular probes for in vivo cancer imaging, but the reported \"always-on\" aptamer probes remain problematic because of high background and limited contrast. To address this problem, we designed an activatable aptamer probe (AAP) targeting membrane proteins of living cancer cells and achieved contrast-enhanced cancer visualization inside mice. The AAP displayed a quenched fluorescence in its free state and underwent a conformational alteration upon binding to target cancer cells with an activated fluorescence. As proof of concept, in vitro analysis and in vivo imaging of CCRF-CEM cancer cells were performed by using the specific aptamer, sgc8, as a demonstration. It was confirmed that the AAP could be specifically activated by target cancer cells with a dramatic fluorescence enhancement and exhibit improved sensitivity for CCRF-CEM cell analysis with the cell number of 118 detected in 200 μl binding buffer. In vivo studies demonstrated that activated fluorescence signals were obviously achieved in the CCRF-CEM tumor sites in mice. Compared to always-on aptamer probes, the AAP could substantially minimize the background signal originating from nontarget tissues, thus resulting in significantly enhanced image contrast and shortened diagnosis time to 15 min. Furthermore, because of the specific affinity of sgc8 to target cancer cells, the AAP also showed desirable specificity in differentiating CCRF-CEM tumors from Ramos tumors and nontumor areas. The design concept can be widely adapted to other cancer cell-specific aptamer probes for in vivo molecular imaging of cancer.

Magnetic resonance imaging (MRI) is a highly valuable diagnostic tool as it is a noninvasive technique that offers high spatial resolution. The use of contrast agents (CAs) can enhance the precision and specificity of MRI for disease diagnosis, but their imaging signals are “always on” regardless of whether they interact with target tissues or cells. Hence, a poor target‐to‐background signal ratio (TBR) is inevitably produced. In contrast, activatable CAs with high performance have been used to significantly improve the TBR, thus these CAs have also received extensive attention and undergone in‐depth research. In this review, we summarized the recent advances in design strategies and principles of activatable MR CAs, including ion conversion, self‐assembly, and disassembly. Additionally, we analyzed the advantages of these strategies in biomedical applications from in vitro biodetection to in vivo disease diagnosis compared to the outcomes of conventional MR CAs. Finally, we discussed the potential limitations, proposed solutions, and future perspectives of these activatable CAs. A comprehensive review is presented on the recent progress of three design strategies (ion extraction, self‐assembly, and disassembly) of activatable MRI probes and highlights their advantages in biomedical applications, including, in vitro biodetection, in vivo imaging and monitoring drug release. It is believed that low‐background imaging techniques are the development trend of MR imaging in the future and the study of activatable MRI probes is one of the key points in this field.

The standard treatment for various types of cancers typically involves the combination of concurrent localized radiotherapy and systemic chemotherapy. However, no treatment options have been reported that utilize chemotherapy cascade-enhanced radiotherapy. In this study, we report a core-satellite nanomedicine designed to enhance radiotherapeutic effects through a cascade mechanism by triggering the release of a potent chemotherapeutic agent in response to trypsin. We synthesized a functional enzyme-sequential responsive nanomedicine, DOX@Gel-DEVD-AuNR, which consists of gelatin nanoparticles loaded with the chemotherapeutic drug doxorubicin (DOX). These nanoparticles are covalently linked to gold nanorods (AuNR) via a caspase-3 specific DEVD peptide substrate. Upon trypsin activation, the DOX@Gel-DEVD-AuNR formulation releases DOX, thereby enhancing chemotherapy efficacy against tumors. Simultaneously, it activates caspase-3, inducing the aggregation of AuNRs, which in turn activates a near-infrared-II photoacoustic signal. This signal is crucial for determining the optimal timing for X-ray irradiation. The resulting large-size AuNRs aggregates promote their accumulation within tumors by preventing the migration and backflow of AuNRs, thereby improving radiotherapeutic effects. Consequently, when combined with image-guided X-ray irradiation, DOX@Gel-DEVD-AuNR induces significant cytotoxicity in cancer cells and effectively inhibits tumor growth. Our study underscores the potential application of enzyme catalysis-mediated chemistry in activating nanomedicine for activatable image-guided chemotherapy cascade-enhanced radiotherapy.

A clear identification of the etiology of glomerular disease is essential in patients with diabetes. Renal biopsy is the gold standard for assessing the underlying nephrotic pathology; however, it has the risk for potential complications. Here, we aimed to investigate the feasibility of urinary fluorescence imaging using an enzyme-activatable probe for differentiating diabetic kidney disease and the other glomerular diseases. Hydroxymethyl rhodamine green (HMRG)-based fluorescent probes targeting gamma-glutamyl transpeptidase (GGT) and dipeptidyl-peptidase (DPP) were used. Urinary fluorescence was compared between groups which were classified by their histopathological diagnoses (diabetic kidney disease, glomerulonephritis, and nephrosclerosis) as obtained by ultrasound-guided renal biopsy. Urinary fluorescence was significantly stronger in patients with diabetic kidney disease compared to those with glomerulonephritis/nephrosclerosis after DPP-HMRG, whereas it was stronger in patients with nephrosclerosis than in patients with glomerulonephritis after GGT-HMRG. Subgroup analyses of the fluorescence performed for patients with diabetes showed consistent results. Urinary fluorescence imaging using enzyme-activatable fluorescence probes thus represents a potential noninvasive assessment technique for kidney diseases in patients with diabetes.

The nonspecific activation of activatable probes presents significant challenges in their applications for accurate cancer detection, leading to false signals in normal tissues and the potential oversight of microlesions. To address this issue, we developed a glutathione (GSH)‐activatable magnetic resonance imaging (MRI) and near‐infrared II (NIR‐II) fluorescent probe (GAP9) using a redox capacity engineering strategy. By systematically adjusting the reaction pH during probe synthesis, we could precisely modulate its oxidation capacity to ensure that the activation window of the probe precisely matched tumor GSH concentrations. This strategy ensures that GAP9 remains in the “OFF” state within normal tissues through dual MRI/NIR‐II quenching mechanisms, minimizing false‐positive signals and background noise. Upon reaching tumor sites, GAP9 undergoes GSH‐triggered disassembly, rapidly activating T1‐weighted MRI for preoperative tumor mapping and unlocking NIR‐II fluorescence for real‐time intraoperative tumor delineation. This tumor‐adaptable strategy enables the specific localization of microtumor lesions, intraoperative margin monitoring, and complete excision of ultrasmall residual foci ≤1 mm, achieving a 96% detection rate in a mouse model of peritoneal metastasis. This study presents a novel paradigm in molecular probe design, emphasizing the potential of integrating programmable redox chemistry with tumor‐specific characteristics to enhance detection accuracy, ultimately improving surgical outcomes and patient prognoses.