It is highly desirable to design a single modality that can simultaneously trigger apoptosis and ferroptosis to efficiently eliminate tumor progression. Herein, a nanosystem based on the intrinsic properties of tumor microenvironment (TME) is designed to achieve tumor control through the simultaneous induction of ferroptosis and apoptosis. CuCP molecules are encapsulated in a liposome‐based nanosystem to assemble into biocompatible and stable CuCP nanoparticles (CuCP Lipo NPs). This nanosystem intrinsically possesses nanozymatic activity and photothermal characteristics due to the property of Cu atoms and the structure of CuCP Lipo NPs. It is demonstrated that the synergistic strategy increases the intracellular lipid‐reactive oxides species, induces the occurrence of ferroptosis and apoptosis, and completely eradicates the tumors in vivo. Proteomics analysis further discloses the key involved proteins (including Tp53, HMOX1, Ptgs2, Tfrc, Slc11a2, Mgst2, Sod1, and several GST family members) and pathways (including apoptosis, ferroptosis, and ROS synthesis). Conclusively, this work develops a strategy based on one nanosystem to synergistically induce ferroptosis and apoptosis in vivo for tumor suppression, which holds great potential in the clinical translation for tumor therapy.

Extracellular vesicles (EVs) are widely used as natural nanoparticles to deliver various cargos for disease diagnosis and therapy. However, unmodified EVs cannot efficiently transport the cargos to desired sites due to non-specific uptake. Here, a delivery system is designed to display nanobodies against cadherin 17 (CDH17) on the surface of EVs isolated from HEK-293 cells and loaded with dye Indocyanine green (ICG) and/or anti-cancer drug dinitroazetidine derivative RRx-001, a blocker for CD47/ signal regulatory protein alpha (SIRPα) axis. CDH17 is a promising target for gastric cancer (GC) therapy. In this study, ICG loaded in the EVs engineered with CDH17 nanobodies can realize rapid tumor imaging in a CDH17-positive GC model and can produce significant antitumor photothermal therapeutic (PTT) effect after irradiation. Meanwhile, PTT effect can induce immunogenic cell death and macrophage polarization from M2 to M1 phenotype. The engineered EVs loaded with RRx-001 can significantly repress GC tumor growth. Finally, dual loading of ICG/RRx-001 in engineered EVs show maximal anti-tumor efficacy in both cancer cell and patient-derived GC models after only single injection. Collectively, CDH17 nanobody-functionalized EVs loaded with ICG and/or RRx-001 hold great promise to image and treat GC by combining fluorescent dye-induced PTT with chemotherapy.

Bacterial infections are common complications for diabetic wounds and represent a considerable challenge for wound therapy. Diabetic wound infections differ from those of normal wounds. Owing to the special microenvironment around them, diabetic wounds are more susceptible to infection and are difficult to heal. Nanozymes are of great significance to treat diabetic wound bacterial infections through unique catalytic activities, particularly for controlling drug-resistant bacteria. However, their intrinsically low catalytic activity largely restricts their bactericidal function. Therefore, it is crucial to design and develop novel antibacterial modalities with multiple mechanisms of action. In this study, we design and synthesize a CeO2/Nb2C nanocomposite with dual functions of peroxidase activity and an excellent near-infrared (NIR) photothermal property. Under 808 nm laser irradiation, the CeO2/Nb2C nanocomposite produced a photothermal antibacterial effect and simultaneously displayed a synergistic enzyme catalytic property, thereby killing bacteria in a sustained manner with more than 80% sterilization ratio. The CeO2/Nb2C nanocomposite could accelerate the recovery of diabetic wounds when the skin lesions infected with methicillin-resistant Staphylococcus aureus (MRSA) were irradiated with an 808 nm laser in a diabetic mouse model. An RNA sequencing assay was used to profile the dynamic transcriptome of MRSA. The data set reveals that bacteria experience dysfunction in energy metabolism, cell morphology, and oxidative stress systems during the treatment with CeO2/Nb2C nanocomposite under NIR irradiation, which further affects their survival. Moreover, the CeO2/Nb2C nanocomposite exhibits good biosafety in vitro and in vivo, which indicates their potency as antibacterial agents. This study provides a novel antibacterial strategy by the combination of the catalytic sterilization with the NIR photothermal activity of nanozymes for the effective treatment of MRSA-related diabetic wound infection.

Background It is highly desirable to develop new therapeutic strategies for gastric cancer given the low survival rate despite improvement in the past decades. Cadherin 17 (CDH17) is a membrane protein highly expressed in cancers of digestive system. Nanobody represents a novel antibody format for cancer targeted imaging and drug delivery. Nanobody targeting CHD17 as an imaging probe and a delivery vehicle of toxin remains to be explored for its theragnostic potential in gastric cancer. Methods Naïve nanobody phage library was screened against CDH17 Domain 1-3 and identified nanobodies were extensively characterized with various assays. Nanobodies labeled with imaging probe were tested in vitro and in vivo for gastric cancer detection. A CDH17 Nanobody fused with toxin PE38 was evaluated for gastric cancer inhibition in vitro and in vivo. Results Two nanobodies (A1 and E8) against human CDH17 with high affinity and high specificity were successfully obtained. These nanobodies could specifically bind to CDH17 protein and CDH17-positive gastric cancer cells. E8 nanobody as a lead was extensively determined for tumor imaging and drug delivery. It could efficiently co-localize with CDH17-positive gastric cancer cells in zebrafish embryos and rapidly visualize the tumor mass in mice within 3 h when conjugated with imaging dyes. E8 nanobody fused with toxin PE38 showed excellent anti-tumor effect and remarkably improved the mice survival in cell-derived (CDX) and patient-derived xenograft (PDX) models. The immunotoxin also enhanced the anti-tumor effect of clinical drug 5-Fluorouracil. Conclusions The study presents a novel imaging and drug delivery strategy by targeting CDH17. CDH17 nanobody-based immunotoxin is potentially a promising therapeutic modality for clinical translation against gastric cancer. Graphical Abstract