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Introduction: The tumor microenvironment (TME) is mainly characterized by abnormally elevated intracellular redox levels and excessive oxidative stress. However, the balance of the TME is also very fragile and susceptible to be disturbed by external factors. Therefore, several researchers are now focusing on intervening in redox processes as a therapeutic strategy to treat tumors. Here, we have developed a liposomal drug delivery platform that can load a Pt(IV) prodrug (DSCP) and cinnamaldehyde (CA) into a pH-responsive liposome to enrich more drugs in the tumor region for better therapeutic efficacy through enhanced permeability and retention effect.Methods: Using the glutathione-depleting properties of DSCP together with the ROS-generating properties of cisplatin and CA, we synergistically altered ROS levels in the tumor microenvironment to damage tumor cells and achieve anti-tumor effects in vitro.Results: A liposome loaded with DSCP and CA was successfully established, and this liposome effectively increased the level of ROS in the tumor microenvironment and achieved effective killing of tumor cells in vitro.Conclusion: In this study, novel liposomal nanodrugs loaded with DSCP and CA provided a synergistic strategy between conventional chemotherapy and disruption of TME redox homeostasis, leading to a significant increase in antitumor effects in vitro.

Treatments for cancer that incorporate small interfering RNA (siRNA) to target iron-dependent ferroptosis are thought to be highly promising. However, creating a reliable and clinically feasible siRNA delivery system continues to be a major obstacle in the field of cancer treatment. Here, three imidazole-based ionizable lipid nanoparticles (LNPs) with pH-sensitive effects are rationally designed and synthesized for siRNA delivery. LNPs formulated with the top-performing lipid (O12-D3-I3) encapsulating FVII siRNA (FVII@O-LNP) elicited greater gene silencing than those with the benchmark Onpattro lipid DLin-MC3-DMA (MC3) due to its stronger endosomal escape. Moreover, Fc-siRNA@O-LNPs encapsulated with ferrocene (Fc) and SLC7A11/Nrf2-targeted siRNA is formulated. The outcomes demonstrate optimal safety profiles and a significant anti-tumor effect by inducing long-lasting and efficient ferroptosis through a synergistic action in vivo. In summary, this work shows that imidazolyl lipid-prepared LNPs are efficient delivery vehicles for cancer therapy and ferroptosis-targeting siRNA administration, both of which have extensive clinical application potential., (© 2024 Wiley‐VCH GmbH.)

Abstract Chemodynamic therapy (CDT) catalyzed by transition metal and starvation therapy catalyzed by intracellular metabolite oxidases are both classic tumor treatments based on nanocatalysts. CDT monotherapy has limitations including low catalytic efficiency of metal ions and insufficient endogenous hydrogen peroxide (H2O2). Also, single starvation therapy shows limited ability on resisting tumors. The “metal-oxidase” cascade catalytic system is to introduce intracellular metabolite oxidases into the metal-based nanoplatform, which perfectly solves the shortcomings of the above-mentioned monotherapiesIn this system, oxidases can not only consume tumor nutrients to produce a “starvation effect”, but also provide CDT with sufficient H2O2 and a suitable acidic environment, which further promote synergy between CDT and starvation therapy, leading to enhanced antitumor effects. More importantly, the “metal-oxidase” system can be combined with other antitumor therapies (such as photothermal therapy, hypoxia-activated drug therapy, chemotherapy, and immunotherapy) to maximize their antitumor effects. In addition, both metal-based nanoparticles and oxidases can activate tumor immunity through multiple pathways, so the combination of the “metal-oxidase” system with immunotherapy has a powerful synergistic effect. This article firstly introduced the metals which induce CDT and the oxidases which induce starvation therapy and then described the “metal-oxidase” cascade catalytic system in detail. Moreover, we highlight the application of the “metal-oxidase” system in combination with numerous antitumor therapies, especially in combination with immunotherapy, expecting to provide new ideas for tumor treatment.

Chemodynamic therapy (CDT) catalyzed by transition metal and starvation therapy catalyzed by intracellular metabolite oxidases are both classic tumor treatments based on nanocatalysts. CDT monotherapy has limitations including low catalytic efficiency of metal ions and insufficient endogenous hydrogen peroxide (H2O2). Also, single starvation therapy shows limited ability on resisting tumors. The "metal-oxidase" cascade catalytic system is to introduce intracellular metabolite oxidases into the metal-based nanoplatform, which perfectly solves the shortcomings of the above-mentioned monotherapiesIn this system, oxidases can not only consume tumor nutrients to produce a "starvation effect", but also provide CDT with sufficient H2O2 and a suitable acidic environment, which further promote synergy between CDT and starvation therapy, leading to enhanced antitumor effects. More importantly, the "metal-oxidase" system can be combined with other antitumor therapies (such as photothermal therapy, hypoxia-activated drug therapy, chemotherapy, and immunotherapy) to maximize their antitumor effects. In addition, both metal-based nanoparticles and oxidases can activate tumor immunity through multiple pathways, so the combination of the "metal-oxidase" system with immunotherapy has a powerful synergistic effect. This article firstly introduced the metals which induce CDT and the oxidases which induce starvation therapy and then described the "metal-oxidase" cascade catalytic system in detail. Moreover, we highlight the application of the "metal-oxidase" system in combination with numerous antitumor therapies, especially in combination with immunotherapy, expecting to provide new ideas for tumor treatment. [ABSTRACT FROM AUTHOR]

Introduction: The tumor microenvironment (TME) is mainly characterized by abnormally elevated intracellular redox levels and excessive oxidative stress. However, the balance of the TME is also very fragile and susceptible to be disturbed by external factors. Therefore, several researchers are now focusing on intervening in redox processes as a therapeutic strategy to treat tumors. Here, we have developed a liposomal drug delivery platform that can load a Pt(IV) prodrug (DSCP) and cinnamaldehyde (CA) into a pH-responsive liposome to enrich more drugs in the tumor region for better therapeutic efficacy through enhanced permeability and retention effect. Methods: Using the glutathione-depleting properties of DSCP together with the ROS-generating properties of cisplatin and CA, we synergistically altered ROS levels in the tumor microenvironment to damage tumor cells and achieve anti-tumor effects in vitro . Results: A liposome loaded with DSCP and CA was successfully established, and this liposome effectively increased the level of ROS in the tumor microenvironment and achieved effective killing of tumor cells in vitro . Conclusion: In this study, novel liposomal nanodrugs loaded with DSCP and CA provided a synergistic strategy between conventional chemotherapy and disruption of TME redox homeostasis, leading to a significant increase in antitumor effects in vitro ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tang, Gong, Gao, Pang, Liu, Xia, Liu, Zhu, Fan and Sun.)

Ultra-thin two-dimensional nanosheets have attracted increasing attention due to their great application prospects in nanomaterial science and biomedicine. Herein, we report the preparation of exfoliated raw and oxidized 4-layer Ti 7 O 13 (O-Ti 7 O 13) and their ability to produce reactive oxygen species (ROS). The results show that O-Ti 7 O 13 nanosheets can effectively produce ROS induced by X-ray irradiation. The 4-layer nanosheets can quickly load doxorubicin (DOX) within 5 min with a high loading rate to obtain a novel nanodrug system through their electrostatic adsorption capacity, and they exhibit a sustained release behavior. In this way, chemotherapy, radiation therapy and photodynamic therapy effectively combine for cancer synergistic treatment. We evaluated the cytotoxicity, cellular uptake and intracellular location of the O-Ti 7 O 13 nanosheet-based drug delivery system in A549 lung cancer cells. Our results show that the O-Ti 7 O 13 /DOX complex is more cytotoxic to A549 cells than free DOX since a low concentration of loaded DOX (10 μg/mL) with a low dose of X-rays can cause the complete apoptosis of tumor cells. This work reveals that the therapeutic effect of DOX-loaded O-Ti 7 O 13 nanosheets is strongly dependent on their loading mode, and the effects of chemotherapy and photodynamic therapy are enhanced under X-ray irradiation, which allows O-Ti 7 O 13 nanosheet use as a photo-activated drug carrier. This work provides a new strategy for preparing 2D metal oxide nanosheets toward biomedical applications. • High dispersed 4-layers O-Ti 7 O 13 nanosheets are synthesized. • O-Ti 7 O 13 nanosheets effectively produce ROS induced by X-ray irradiation. • O-Ti 7 O 13 nanosheets show pH-responsive behavior in DOX drug loading and release. • Killing rate of A549 cells is near 100% by O-Ti 7 O 13 -DOX under X-ray irradiation. • Tumor synergistic therapy is achieved by O-Ti 7 O 13 based drug delivery system. [ABSTRACT FROM AUTHOR]

Mesoporous titanium peroxide TiO x nanospheres with a high surface area are synthesized for the application of an advanced drug system. The mesoporous TiO x nanospheres have a high specific surface area of 681.89 m 2 /g and suitable pore size (∼3 nm) that can effectively upload doxorubicin (DOX) and possesses a high drug storage capacity of 146.08%. They show a distinct ability to produce reactive oxygen species (ROS) in response to X-ray irradiation, which can effectively improve the radiotherapy in tumor treatment using the lung cancer cell line. The ROS generation of TiO x is more than ten-fold higher than that of TiO 2 . No apparent toxicity is found for the TiO x material itself without X-ray irradiation. In vitro and in vivo experiments show that TiO x /DOX nanodrugs significantly enhance cytotoxicity in response to X-ray irradiation. CCK8 assays display that the TiO x /DOX nanodrug has higher cancer treatment efficiency in response to X-ray irradiation because of the synergistic effect of chemotherapy and generation of ROS. In the in vivo experiments using lung cancer tumor-bearing mice model, the tumor inhibition rate in the TiO x /DOX + X-ray group increased by 90.4% compared to the untreated control group, showing a good synergistic chemo-radiotherapy effect in tumor treatment.