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Cuproptosis has drawn enormous attention in antitumor material fields; however, the responsive activation of cuproptosis against tumors using nanomaterials with high atom utilization is still challenging. Herein, a copper-based nanoplatform consisting of acid-degradable copper hydride (CuH) nanoparticles was developed via a microfluidic synthesis. After coating with tumor-targeting hyaluronic acid (HA), the nanoplatform denoted as HA-CuH-PVP (HCP) shows conspicuous damage toward tumor cells by generating Cu + and hydrogen (H 2 ) simultaneously. Cu + can induce apoptosis by relying on Fenton-like reactions and lead to cuproptosis by causing mitochondrial protein aggregation. Besides, the existence of H 2 can enhance both cell death types by causing mitochondrial dysfunction and intracellular redox homeostatic disorders. In vivo experimental results further exhibit the desirable potential of HCP for killing tumor cells and inhibiting lung metastases, which will broaden the horizons of designing copper-based materials triggering apoptosis and cuproptosis for better antitumor efficacy.

As a promising therapeutic strategy against cancer, immunotherapy faces critical challenges, especially in solid tumors. Immune checkpoint blockade therapy, particularly blocking the interaction of the programmed cell death 1 (PD1)-PD1 ligand 1 (PD-L1) axis, can reverse the suppression of T cells so as to destroy tumor cells and exert antitumor effects. Here, a strategy of multiple activation of immune pathways is developed, to provide supporting evidence for potential antitumor therapies. Briefly, a pH/glutathione responsive drug-loading hollow-manganese dioxide (H-MnO 2 )-based chlorine6 (Ce6)-modified DNAzyme therapeutic nanosystem for the combination of gene therapy and immunotherapy is established. The H-MnO 2 nanoparticles could efficiently deliver the DNAzyme and glycyrrhizic acid (GA) to enhance the tumor target effects. In the tumor microenvironments, the biodegradation of H-MnO 2 via pH-induced hydrolyzation allows the release of guest DNAzyme payloads and host Mn 2+ ions, which serve as PD-L1 mRNA-targeting reagent and require DNAzyme cofactors for activating gene therapy. In addition, Mn 2+ is also associated with the immune activation of thcGAS-STING pathway. Auxiliary photosensitizers Ce6 and GA could produce reactive oxygen species, resulting in immunogenic cell death. Overall, this study provides a general strategy for targeted gene inhibition and GA release, which is valuable for the development of potential tumor immunotherapies., (© 2022 Wiley-VCH GmbH.)

Recently, multifunctional clearable inorganic theranostic nanoparticles have been attracting more and more attention. Protein-based nanoparticles can be cleared by the hepatobiliary system efficiently. In this work, ultrasmall gadolinium oxide (Gd 2 O 3 ) nanoparticles, which possess the advantage of high longitudinal relaxation rate, were coated with bovine serum albumin (BSA). After the Gd 2 O 3 /BSA nanoparticles were linked with two-dimensional photothermal MoS 2 nanomaterials, the nanoparticles were also modified with hyaluronic acid (HA) through the disulfide bonds for tumor-targeting effect. As indicated by in vitro and in vivo studies, these Gd 2 O 3 /BSA@MoS 2 -HA nanoparticles could be rapidly degraded and excreted after reacting with glutathione (GSH) by the redox response, thus avoiding long-term toxicity. In addition, the cellular uptake study and in vivo multispectral optoacoustic tomography (MSOT), X-ray computed tomography (CT), and magnetic resonance (MR) triple-modal images demonstrated that Gd 2 O 3 /BSA@MoS 2 -HA nanoparticles exhibited a high tumor uptake effect after intravenous injection. Consequently, such clearable theranostic nanoparticles with multiple functions, which are applicable in multimodal imaging-guided cancer therapy, might show promise for applications in nanomedical science.

Radiotherapy (RT) is one of the most widely applied treatments for cancer therapy in clinics. Herein, we constructed innovative multifunctional nanotheranostic MnO2-mSiO2@Au-HA nanoparticles (MAHNPs) based on one-pot MnO2-mSiO2 nanohybrids (MNHs) and gold nanoparticles (AuNPs) for multispectral optoacoustic tomography (MSOT)/computed tomography (CT) and magnetic resonance (MR) imaging-guided hypoxia-maneuvered radiotherapy. The MNHs were prepared via a facile one-pot approach, which avoided the leakage of MnO2 nanoparticles and increased the synthetic efficiency. The Mn2+ ions triggered the breakdown of endogenous H2O2 to generate O2 to convert the hypoxic tumor micro-environment (TME), thus enhancing radiotherapy by self-supply oxygen. In addition, hyaluronic acid (HA) was employed to modify the surface of the MnO2-mSiO2@Au nanoparticles to improve their biocompatibility and cellular uptake. The well-designed nanoparticles could perform remarkable photothermal therapy (PTT) and hypoxia-maneuvered radiotherapy (RT) simultaneously and MSOT/CT/MR imaging. The in vivo studies showed that the MAHNPs achieved almost total suppression of tumor growth without observable recurrence, which raises new possibilities for clinical nanotheranostics with multimodal diagnostic and therapeutic coalescent design.