Ruifang Wang’s research while affiliated with Wuhan National High Magnetic Field Center and other places

The immune checkpoint blockade strategy has improved the survival rate of late‐stage lung cancer patients. However, the low immune response rate limits the immunotherapy efficiency. Here, we report a ROS‐responsive Fe3O4‐based nanoparticle that undergoes charge reversal and disassembly in the tumor microenvironment, enhancing the uptake of Fe3O4 by tumor cells and triggering a more severe ferroptosis. In the tumor microenvironment, the nanoparticle rapidly disassembles and releases the loaded GOx and the immune‐activating peptide Tuftsin under overexpressed H2O2. GOx can consume the glucose of tumor cells and generate more H2O2, promoting the disassembly of the nanoparticle and drug release, thereby enhancing the therapeutic effect of ferroptosis. Combined with Tuftsin, it can more effectively reverse the immune‐suppressive microenvironment and promote the recruitment of effector T cells in tumor tissues. Ultimately, in combination with α‐PD‐L1, there is significant inhibition of the growth of lung metastases. Additionally, the hyperpolarized ¹²⁹Xe method has been used to evaluate the Fe3O4 nanoparticle‐mediated immunotherapy, where the ventilation defects in lung metastases have been significantly improved with complete lung structure and function recovered. The ferroptosis‐enhanced immunotherapy combined with non‐radiation evaluation methodology paves a new way for designing novel theranostic agents for cancer therapy.

The immune checkpoint blockade strategy has improved the survival rate of late‐stage lung cancer patients. However, the low immune response rate limits the immunotherapy efficiency. Here, we report a ROS‐responsive Fe3O4‐based nanoparticle that undergoes charge reversal and disassembly in the tumor microenvironment, enhancing the uptake of Fe3O4 by tumor cells and triggering a more severe ferroptosis. In the tumor microenvironment, the nanoparticle rapidly disassembles and releases the loaded GOx and the immune‐activating peptide Tuftsin under overexpressed H2O2. GOx can consume the glucose of tumor cells and generate more H2O2, promoting the disassembly of the nanoparticle and drug release, thereby enhancing the therapeutic effect of ferroptosis. Combined with Tuftsin, it can more effectively reverse the immune‐suppressive microenvironment and promote the recruitment of effector T cells in tumor tissues. Ultimately, in combination with α‐PD‐L1, there is significant inhibition of the growth of lung metastases. Additionally, the hyperpolarized 129Xe method has been used to evaluate the Fe3O4 nanoparticle‐mediated immunotherapy, where the ventilation defects in lung metastases have been significantly improved with complete lung structure and function recovered. The ferroptosis‐enhanced immunotherapy combined with non‐radiation evaluation methodology paves a new way for designing novel theranostic agents for cancer therapy.

Despite its remarkable clinical breakthroughs, immune checkpoint blockade (ICB) therapy remains limited by the insufficient immune response in the “cold” tumor. Nanozyme‐based antitumor catalysis is associated with precise immune activation in the tumor microenvironment (TME). In this study, a cascade‐augmented nanoimmunomodulator (CMZM) with multienzyme‐like activities, which includes superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione oxidase (GSHOx), that dissociates under an acidic and abundant GSH TME, is proposed for multimodal imaging‐guided chemodynamic therapy (CDT)/photodynamic therapy (PDT) enhanced immunotherapy. Vigorous multienzyme‐like activities can not only produce O 2 to alleviate hypoxia and promote the polarization of M2 to M1 macrophages but also generate ROS (•OH and ¹ O 2 ) and deplete GSH in the TME to expose necrotic cell fragments and reverse immunosuppressive TME by eliciting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes in tumors. Therefore, inhibitory effects on both primary and distant tumors were achieved through synergy with an α‐PD‐L1 blocking antibody. This cascade multienzyme‐based nanoplatform provides a smart strategy for highly efficient ICB immunotherapy against “cold” tumors by revising immunosuppressive TME. This article is protected by copyright. All rights reserved

To realize sensing and labeling biomarkers is quite challenging in terms of designing multimodal imaging probes. In this study, we developed a novel β‐galactosidase (β‐gal) activated bimodal imaging probe that combines near‐infrared (NIR) fluorescence and magnetic resonance imaging (MRI) to enable real‐time visualization of activity in living organisms. Upon β‐gal activation, Gal‐Cy‐Gd‐1 exhibits a remarkable 42‐fold increase in NIR fluorescence intensity at 717 nm, allowing covalent labeling of adjacent target enzymes or proteins and avoiding molecular escape to promote probe accumulation at the tumor site. This fluorescence reaction enhances the longitudinal relaxivity by approximately 1.9 times, facilitating high‐resolution MRI. The unique features of Gal‐Cy‐Gd‐1 enable real‐time and precise visualization of β‐gal activity in live tumor cells and mice. The probe's utilization aids in identifying in situ ovarian tumors, offering valuable assistance in the precise removal of tumor tissue during surgical procedures in mice. The fusion of NIR fluorescence and MRI activation through self‐immobilizing target enzymes or proteins provides a robust approach for visualizing β‐gal activity. Moreover, this approach sets the groundwork for developing other activatable bimodal probes, allowing real‐time in vivo imaging of enzyme activity and localization.

To realize sensing and labeling biomarkers is quite challenging in terms of designing multimodal imaging probes. In this study, we developed a novel β ‐galactosidase ( β ‐gal) activated bimodal imaging probe that combines near‐infrared (NIR) fluorescence and magnetic resonance imaging (MRI) to enable real‐time visualization of activity in living organisms. Upon β ‐gal activation, Gal‐Cy‐Gd‐1 exhibits a remarkable 42‐fold increase in NIR fluorescence intensity at 717 nm, allowing covalent labeling of adjacent target enzymes or proteins and avoiding molecular escape to promote probe accumulation at the tumor site. This fluorescence reaction enhances the longitudinal relaxivity by approximately 1.9 times, facilitating high‐resolution MRI. The unique features of Gal‐Cy‐Gd‐1 enable real‐time and precise visualization of β ‐gal activity in live tumor cells and mice. The probe's utilization aids in identifying in situ ovarian tumors, offering valuable assistance in the precise removal of tumor tissue during surgical procedures in mice. The fusion of NIR fluorescence and MRI activation through self‐immobilizing target enzymes or proteins provides a robust approach for visualizing β ‐gal activity. Moreover, this approach sets the groundwork for developing other activatable bimodal probes, allowing real‐time in vivo imaging of enzyme activity and localization.

Nanohybrids have gained immense popularity for the diagnosis and chemotherapy of lung cancer for their excellent biocompatibility, biodegradability, and targeting ability. However, most of them suffer from limited imaging information, low tumor-to-background ratios, and multidrug resistance, limiting their potential clinical application. Herein, we engineered a photoresponsive nanohybrid by assembling polypyrrole@bovine serum albumin (PPy@BSA) encapsulating perfluoropentane (PFP)/129Xe for selective magnetic resonance (MR)/ultrasonic (US)/photoacoustic (PA) trimodal imaging and photothermal therapy of lung cancer, overcoming these drawbacks of single imaging modality and chemotherapy. The nanohybrid exhibited superior US, PA, and MR multimodal imaging performance for lung cancer detection. The high sensitivity of the nanohybrid to near-infrared light (NIR) resulted in a rapid increase in temperature in a low-intensity laser state, which initiated the phase transition of liquid PFP into the gas. The ultrasound signal inside the tumor, which is almost zero initially, is dramatically increased. Beyond this, it led to the complete depression of 19F/129Xe Hyper-CEST (chemical exchange saturation transfer) MRI during laser irradiation, which can precisely locate lung cancer. In vitro and in vivo results of the nanohybrid exhibited a successful therapeutic effect on lung cancer. Under the guidance of imaging results, a sound effect of photothermal therapy (PTT) for lung cancer was achieved. We expect this nanohybrid and photosensitive behavior will be helpful as fundamental tools to decipher lung cancer in an earlier stage through trimodality imaging methods.