Bioinspired Nano-Photosensitizer-Activated Caspase-3/GSDME Pathway Induces Pyroptosis in Lung Cancer Cells.

Noninflammatory apoptosis is transformed into inflammatory pyroptosis by activating caspase-3 to lyse gasdermin E (GSDME), and this process can be used as an effective therapeutic strategy. Thus, a selective and powerful inducer of activated caspase-3 plays a vital role in pyroptosis-based cancer therapy. Herein, a human cell membrane vesicle-based nanoplatform (HCNP) is designed for photodynamic therapy (PDT). HCNP is modified with vesicular stomatitis virus G-protein (VSVG) to anchor nano-photosensitizers on the tumor cell membrane. Photosensitizers are bonded to HCNP by clicking chemical reaction as pyroptosis inducers. The results show that HCNP effectively disrupts the mitochondrial function of cells by generating reactive oxygen species (ROS) upon laser irradiation; concomitantly, GSDME is cleaved by activated caspase-3 and promotes pyroptosis of lung cancer cells. Here an effective intervention strategy is proposed to induce pyroptosis based on light-activated PDT.

Advancing Precision: A Controllable Self-Synergistic Nanoplatform Initiating Pyroptosis-Based Immunogenic Cell Death Cascade for Targeted Tumor Therapy.

Heterogeneity of the tumor microenvironment (TME) is primarily responsible for ineffective tumor treatment and uncontrolled tumor progression. Pyroptosis-based immunogenic cell death (ICD) therapy is an ideal strategy to overcome TME heterogeneity and obtain a satisfactory antitumor effect. However, the efficiency of current pyroptosis therapeutics, which mainly depends on a single endogenous or exogenous stimulus, is limited by the intrinsic pathological features of malignant cells. Thus, it is necessary to develop a synergistic strategy with a high tumor specificity and modulability. Herein, a synergistic nanoplatform is constructed by combining a neutrophil camouflaging shell and a self-synergistic reactive oxygen species (ROS) supplier-loaded polymer. The covered neutrophil membranes endow the nanoplatform with stealthy properties and facilitate sufficient tumor accumulation. Under laser irradiation, the photosensitizer (indocyanine green) exogenously triggers ROS generation and converts the laser irradiation into heat to upregulate NAD(P)H:quinone oxidoreductase 1, which further catalyzes ß-Lapachone to self-produce sufficient endogenous ROS, resulting in amplified ICD outcomes. The results confirm that the continuously amplified ROS production not only eliminates the primary tumor but also concurrently enhances gasdermin E-mediated pyroptosis, initiates an ICD cascade, re-educates the heterogeneous TME, and promotes a systemic immune response to suppress distant tumors. Overall, this self-synergistic nanoplatform provides an efficient and durable method for redesigning the immune system for targeted tumor inhibition.

Biomimetic Nanophotosensitizer Amplifies Immunogenic Pyroptosis and Triggers Synergistic Cancer Therapy.

Immunotherapy is considered to be an effective treatment for cancer and has drawn extensive interest. Nevertheless, the insufficient antigenicity and immunosuppressive tumor microenvironment often cause unsatisfactory therapeutic efficacy. Herein, a photo-activated reactive oxygen species (ROS) amplifying system (defined as "M-Cu-T") is developed to induce antitumor immune response by triggering a tumor-specific immunogenic pyroptosis. In M-Cu-T, M1 macrophage membrane-based vesicles are used for drug loading and tumor targeting, photosensitizers (meso-tetra(4-aminophenyl) porphyrin, TAPP) are used as a pyroptosis inducer, copper ions (Cu2+ ) can enhance ROS-induced pyroptosis by consuming antioxidant systems in cells. As expected, the prepared M-Cu-T targets enrichment into tumor cells and cascades the generation of ROS, which further induces pyroptosis through caspase 3-mediated gasdermin E (GSDME) cleavage under laser activation. The pyroptotic cancer cells accompanying secrete related pattern molecules, induce immunogenic cell death, and activate antitumor immunity for immunotherapy. An effective tumor ablation is observed in LLC and CT26 cancer mouse models. This study provides inspiration for boosting the immunogenicity and achieving satisfactory therapeutic effects in cancer therapy.

Diagnostic value of MDM2 RNA in situ hybridization for low-grade osteosarcoma: Consistency comparison of RNA in situ hybridization, fluorescence in situ hybridization, and immunohistochemistry.

Detection of MDM2 gene amplification via fluorescence in situ hybridization (FISH) and MDM2 overexpression by immunohistochemistry (IHC) have been utilized for the diagnosis of low-grade osteosarcoma (LGOS). The aim of this study was to evaluate the diagnostic value of MDM2 RNA in situ hybridization (RNA-ISH) and compare this assay with MDM2 FISH and IHC in distinguishing LGOS from its histologic mimics. MDM2 RNA-ISH, FISH and IHC were performed on nondecalcified samples of 23 LGOSs and 52 control cases. Twenty (20/21, 95.2%) LGOSs were MDM2-amplified, and two cases failed in FISH. All control cases were MDM2-nonamplified. All 20 MDM2-amplified LGOSs and one MDM2-nonamplified LGOS harboring TP53 mutation and RB1 deletion showed positivity for RNA-ISH. Fifty of the 52 (96.2%) control cases were negative for RNA-ISH. The diagnostic sensitivity and specificity of MDM2 RNA-ISH were 100.0% and 96.2%, respectively. Nineteen of the 23 LGOSs were evaluated by MDM2 RNA-ISH and FISH in decalcified samples simultaneously. All decalcified LGOSs failed in FISH and most samples (18/19) were no staining in RNA-ISH. Fifteen (15/20, 75%) MDM2-amplified LGOSs were positive for IHC and 96.2% (50/52) of control cases were negative. The sensitivity of RNA-ISH (100%) was higher than that of IHC (75%). In conclusion, MDM2 RNA-ISH has great value for the diagnosis of LGOS, with excellent consistency with FISH and better sensitivity than IHC. Acid decalcification still has an adverse impact on RNA. Some MDM2-nonamplified tumors may show positivity for MDM2 RNA-ISH, which needs to be analyzed comprehensively in combination with clinicopathological features.

Carrier-Free H2 O2 Self-Supplier for Amplified Synergistic Tumor Therapy.

Chemodynamic therapy (CDT) utilizes Fenton or Fenton-like reactions to convert hydrogen peroxide (H2 O2 ) into cytotoxic hydroxyl radicals (•OH) and draws extensive interest in tumor therapy. Nevertheless, high concentrations of glutathione (GSH) and insufficient endogenous H2 O2 often cause unsatisfactory therapeutic efficacy. Herein, a GSH-depleting and H2 O2 self-providing carrier-free nanomedicine that can efficiently load indocyanine green (ICG), ß-lapachone (LAP), and copper ion (Cu2+ ) (ICG-Cu2+ -LAP, LICN) to mediate synergetic photothermal and chemotherapy in enhanced chemodynamic therapy is designed. The results show that  LICNs successfully enter tumors owing to the enhanced permeability and retention effect. Through the reductive intracellular environment, Cu2+ in LICN can react with intracellular GSH, alleviate the antioxidant capacity of tumor tissues, and trigger the release of drugs. When LICN is subjected to near-infrared (NIR) irradiation, enhanced photothermal effect and upregulated expression of NAD(P)H quinone oxidoreductase-1 (NQO1) are observed. Meanwhile, the released LAP not only supports chemotherapy but also catalyzes NQO1 and produces sufficient endogenous H2 O2 , thereby increasing the efficiency of Cu+ -based Fenton-like reaction. Notably, GSH depletion and H2 O2 self-sufficiency generate sufficient •OH and kill tumor cells with high specificity. Overall, the study provides an innovative strategy to self-regulate GSH and H2 O2 levels for effective anticancer therapy.

Cell Membrane-Anchoring Nano-Photosensitizer for Light-Controlled Calcium-Overload and Tumor-Specific Synergistic Therapy.

Poor selectivity and unintended toxicity to normal organs are major challenges in calcium ion (Ca2+ ) overload tumor therapy. To address this issue, a cell membrane-anchoring nano-photosensitizer (CMA-nPS) is constructed for inducing tumor-specific Ca2+ overload through multistage endogenous Ca2+ homeostasis disruption under light guidance, i.e., the extracellular Ca2+ influx caused by cell membrane damage, followed by the intracellular Ca2+ imbalance caused by mitochondrial dysfunction. CMA-nPS is decorated by two types of functionalized cell membranes, the azide-modified macrophage cell membrane is used to conjugate the dibenzocyclooctyne-decorated photosensitizer, and the vesicular stomatitis virus glycoprotein (VSV-G)-modified NIH3T3 cell membrane is used to guide the anchoring of photosensitizer to the lung cancer cell membrane. The in vitro study shows that CMA-nPS mainly anchors on the cell membrane, and further causes membrane damage, mitochondrial dysfunction, as well as intracellular Ca2+ overload upon light irradiation. Synergistically enhanced antitumor efficiency is observed in vitro and in vivo. This study provides a new synergistic strategy for Ca2+ -overload-based cancer therapy, as well as a strategy for anchoring photosensitizer on the cell membrane, offering broad application prospects for the treatment of lung cancer.