Zhiming Deng

Metformin as a hypoglycemic drug for antidiabetic treatment has emerged as a multipotential drug for many disease treatments such as cognitive disorders, cancers, promoting weight loss. However, overdose uptake may upregulate the hepatic H2S level, subsequently leading to serious liver injury and toxicity. Therefore, developing intelligent second near-infrared (NIR-II) emitting nanoprobes by using endogenous H2S as a smart trigger for noninvasive highly specific in situ monitoring of the metformin-induced hepatotoxicity is highly desirable, which is rarely explored. Herein, an endogenous H2S activated orthogonal NIR-II emitting myrica rubra-like nanoprobe based on NaYF4:Gd/Yb/Er@NaYF4:Yb@SiO2 coated with Ag nanodots was explored for highly specific in vivo ratiometrically monitoring of hepatotoxicity. The designed nanoprobes were mainly uptaken by the liver and subsequently converted to NaYF4:Gd/Yb/Er@NaYF4:Yb@SiO2@Ag2S via in situ sulfuration reaction triggered by the overexpressed endogenous H2S in the injured liver tissues, finally leading to a turn-on orthogonal emission centered at 1053 nm (irradiation by 808 nm laser) and 1525 nm (irradiation by 980 nm laser). The designed nanoprobe presents a high detection limit down to 0.7 nM of H2S. More importantly, the in situ highly specific ratiometric imaging of the metformin-induced hepatotoxicity was successfully achieved by using the activatable orthogonal NIR-II emitting probe. Our results provide an NIR-II ratiometric fluorescence imaging strategy for highly sensitive/specific diagnosis of hepatotoxicity levels induced by metformin.

Abstract Lanthanide based upconversion (UC) nanoprobes have emerged as promising agents for biological applications. Extending the excitation light to the second near‐infrared (NIR‐II), instead of the traditional 980/808 nm light, and realizing NIR‐II responsive single‐band red UC emission is highly demanded for bioimaging application, which has not yet been explored. Here, a new type of NIR‐II (1532 nm) light responsive UC nanoparticles (UCNPs) with enhanced single‐band red UC emission and controllable phase and size is designed by introducing Er 3+ as sensitizer and utilizing Mn 2+ as energy manipulator. Through tuning the content of Mn 2+ in NaLnF 4 :Er/Mn, the crystal phase, size, and emitting color are readily controlled, and the red‐to‐green (R/G) ratio is significantly increased from ≈20 to ≈300, leading to NIR‐II responsive single band red emission via efficient energy transfer between Er 3+ and Mn 2+ . In addition, the single band red emitting intensity can be further improved by coating shell to avoid the surface quenching effect. More importantly, NIR‐II light activated red UC bioimaging and photodynamic therapy through loading photosensitizer of zinc phthalocyanine are successfully achieved for the first time. These findings provide a new strategy of designing NIR‐II light responsive single‐band red emissive UCNPs for biomedical applications.

Recently, oncolytic virus (OV) therapy has shown great promise in treating malignancies. However, intravenous safety and inherent lack of immunity are two significant limitations in clinical practice. Herein, we successfully developed a recombinant Newcastle disease virus with porcine α1,3GT gene (NDV-GT) triggering hyperacute rejection. We demonstrated its feasibility in preclinical studies. The intravenous NDV-GT showed superior ability to eradicate tumor cells in our innovative CRISPR-mediated primary hepatocellular carcinoma monkeys. Importantly, the interventional clinical trial treating 20 patients with relapsed/refractory metastatic cancer (Chinese Clinical Trial Registry of WHO, ChiCTR2000031980) showed a high rate (90.00%) of disease control and durable responses, without serious adverse events and clinically functional neutralizing antibodies, further suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of NDV-GT for immunovirotherapy. Collectively, our results demonstrate the high safety and efficacy of intravenous NDV-GT, thus providing an innovative technology for OV therapy in oncological therapeutics and beyond.

Abstract Gas‐based therapy has emerged as a new green therapy strategy for anti‐tumor treatment. However, the therapeutic efficacy is still restricted by the deep tissue controlled release, poor lymphocytic infiltration, and inherent immunosuppressive tumor microenvironment (TME). Herein, a new type of nanovaccine is designed by integrating low dose soft X‐ray‐triggered CO releasing lanthanide scintillator nanoparticles (ScNPs: NaLuF 4 :Gd,Tb@NaLuF 4 ) with photo‐responsive CO releasing moiety (PhotoCORM) for synergistic CO gas/immuno‐therapy of tumors. The designed nanovaccine presents significantly boosted radioluminescence and enables deep tissue CO generation at unprecedented tissue depths of 5 cm under soft X‐ray irradiation. Intriguingly, CO as a superior immunogenic cell death (ICD) inducer further reverses the deep tissue immunosuppressive TME and concurrently activates adaptive anti‐tumor immunity through efficient reactive oxygen species (ROS) generation. More importantly, the designed nanovaccine presents efficient growth inhibition of both local and distant tumors via a soft X‐ray activated systemic anti‐tumor immunoresponse. This work provides a new strategy of designing anti‐tumor nanovaccines for synergistic deep tissue gas‐therapy and remote soft X‐ray photoactivation of the immune response.