properties with low immunogenicity and the infiltration of T cells. [3] Therefore, strategies by which "cold" tumors can be transformed into "hot" tumors have been extensively researched so that more patients may obtain the benefits of ICBs therapy. The immunogenic cell death (ICD) of tumors has been proved to be an effective tool to improve the immunogenicity of tumor cells. [4] ICD occurs when specific inducers harness the host immune system to recognize and kill cancer cells by causing endoplasmic reticulum (ER) stress. [5] The dying tumor cells release damage-associated molecular patterns (DAMPs), which primarily consist of calreticulin (CRT), high mobility group box 1 (HMGB1), adenosine triphosphate (ATP), and heat shock protein 70 (HSP70). [6] Previous literature revealed that the antigen presentation efficiency of dendritic cells (DCs) was positively correlated with the DAMP content in tumors; [7] therefore, the sufficient release of DAMPs from tumor cells undergoing ICD is crucial to improve immunotherapy efficiency. Apart from the low immunogenicity of tumor cells, the counteracted innate immune system is also responsible for the poor therapeutic effect of ICBs. The suppressive immune cells in tumors, including tumor-associated macrophages (TAMs) and regulatory T cells (Tregs), always lead to immunotherapy failure because they limit T cell infiltration Immunogenic cell death (ICD) has aroused widespread attention because it can reconstruct a tumor microenvironment and activate antitumor immunity. This study proposes a two-way enhancement of ICD based on aCaO 2 @CuS-MnO 2 @HA (CCMH) nanocomposite to overcome the insufficient damageassociated molecular patterns (DAMPs) of conventional ICD-inducers. The near-infrared (NIR) irradiation (1064 nm) of CuS nanoparticles generates 1 O 2 through photodynamic therapy (PDT) to trigger ICD, and it also damages the Ca 2+ buffer function of mitochondria. Additionally, CaO 2 nanoparticles react with H 2 O to produce a large amount of O 2 and Ca 2+ , which respectively lead to enhanced PDT and Ca 2+ overload during mitochondrial damage, thereby triggering a robust ICD activation. Moreover, oxidative-damaged mitochondrial DNA, induced by PDT and released from tumor cells, reprograms the immunosuppressive tumor microenvironment by transforming tumor-associated macrophages to the M1 subphenotype. This study shows that CCMH with NIR-II irradiation can elicit adequate DAMPs and an active tumorimmune microenvironment for both 4T1 and CT26 tumor models. Combining this method with an immune checkpoint blockade can realize an improved immunotherapy efficacy and long-term protection effect for body.
Brain glucose is an important biomarker of Alzheimer's disease (AD) and has a high specificity especially for early AD. Activatable magnetic resonance imaging (MRI) contrast agents (CAs) serve as a robust technology in the early diagnosis of many diseases; however, there is a lack of glucose-specific MRI CAs. To address this issue, in this work, we synthesized a novel MRI CA (ZIF-8/GOx@MnO 2 @PEG, ZGMP) that consists of porous zeolitic imidazolate framework-8 (ZIF-8) attached with glucose oxidase (GOx) and modified by MnO 2 and PEG. The cascade reaction of brain glucose with ZGMP could result in the production of Mn(II) and an enhanced MRI signal. An early AD mouse model was constructed through injection of the Aβ42 oligomer into the parenchyma of mice and utilized to verify the brain glucose activated MRI of ZGMP. The results indicated a higher glucose uptake in early AD mice compared to that in normal mice, with an obviously enhanced T 1 WI at the region of interest. This work gets rid of the need for a specific scanning sequence for glucose MRI, paving a convenient way for MRI diagnosis of early AD.
The imaging resolution of magnetic resonance imaging (MRI) is influenced by many factors. The development of more effective MRI contrast agents (CAs) is significant for early tumor detection and radical treatment, albeit challenging. In this work, the Hofmeister effect of Fe2O3 nanoparticles within the tumor microenvironment was confirmed for the first time. Based on this discovery, we designed a nanocomposite (FePN) by loading Fe2O3 nanoparticles on black phosphorus nanosheets. After reacting with glutathione, the FePN will undergo two stages in the tumor microenvironment, resulting in the robust enhancement of r 1 and r 2 based on the Hofmeister effect in the commonly used magnetic field (3.0 T). The glutathione-activated MRI signal of FePN was higher than most of the activatable MRI CAs, enabling a more robust visualization of tumors. Furthermore, benefiting from the long circulation time of FePN in the blood and retention time in tumors, the synergistic therapy of FePN exhibited an outstanding inhibition toward tumors. The FePN with good biosafety and biocompatibility will not only pave a new way for designing a common magnetic field-tailored T 1 –T 2 dual-mode MRI CA but also offer a novel pattern for the accurate clinical diagnosis and therapy of tumors.
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