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Advancing Precision: A Controllable Self-Synergistic Nanoplatform Initiating Pyroptosis-Based Immunogenic Cell Death Cascade for Targeted Tumor Therapy. ACS nano 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 β-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. 10.1021/acsnano.3c09499
Tumor Microenvironment-Responsive Yolk-Shell NaCl@Virus-Inspired Tetrasulfide-Organosilica for Ion-Interference Therapy Osmolarity Surge and Oxidative Stress Amplification. ACS nano Ion-interference therapy, which utilizes ions to disturb intracellular biological processes, provides inspiration for tumor therapy. Artificially reversing osmotic pressure by transporting large amounts of physiological ions to tumor cells is a straightforward yet low-toxic strategy for ion-interference therapy. However, it is hard to achieve due to the serious limitations of single-ion delivery. Herein, we skillfully deliver NaCl nanocrystals to tumor sites and sequentially realize the explosive release of Na/Cl inside tumor cells by utilizing a virus-mimicking and glutathione (GSH)-responsive hollow mesoporous tetrasulfide-bridged organosilica (ssss-VHMS). Once the ssss-VHMS-wrapped NaCl nanocrystals (NaCl@ssss-VHMS) accumulate in the tumors, they would rapidly invade tumor cells spike surface-assisted endocytosis, thus bypassing Na/K-ATPase transmembrane ion transporters. Afterward, the intracellular overproduced GSH of tumor cells would trigger the rapid degradation of ssss-VHMS thiol-tetrasulfide exchange, which could not only remarkably deplete the GSH but also explosively release the Na/Cl, leading to the osmolarity surge accompanied by reactive oxygen species (ROS) generation. The cell swelling, ROS storm, and GSH exhaustion of NaCl@ssss-VHMS effectively eradicated tumor cells by caspase-1-dependent pyroptosis, caspase-3-dependent apoptosis, and GPX4-dependent ferroptosis, respectively, thus synergistically inhibiting tumor growth. We believe that NaCl@ssss-VHMS would be a potential cancer therapeutic agent, and this discovery could provide a perspective for exploring synergistic ion-interference therapy. 10.1021/acsnano.1c09496
Metal-Organic Framework-Based Nanovaccine for Relieving Immunosuppressive Tumors via Hindering Efferocytosis of Macrophages and Promoting Pyroptosis and Cuproptosis of Cancer Cells. ACS nano Current cancer vaccines face challenges due to an immunosuppressive tumor microenvironment and their limited ability to produce an effective immune response. To address the above limitations, we develop a 3-(2-spiroadamantyl)-4-methoxy-4-(3-phosphoryloxy)-phenyl-1,2-dioxetane (alkaline phosphatase substrate) and XMD8-92 (extracellular signal-regulated kinase 5 inhibitor)-codelivered copper-tetrahydroxybenzoquinone (Cu-THBQ/AX) nanosized metal-organic framework to in situ-generate therapeutic vaccination. Once inside the early endosome, the alkaline phosphatase overexpressed in the tumor cells' membrane activates the in situ type I photodynamic effect of Cu-THBQ/AX for generating O, and the Cu-THBQ/AX catalyzes O and HO to O and OH via semiquinone radical catalysis and Fenton-like reactions. This surge of ROS in early endosomes triggers caspase-3-mediated proinflammatory pyroptosis via activating phospholipase C. Meanwhile, Cu-THBQ/AX can also induce the oligomerization of dihydrolipoamide S-acetyltransferase to trigger tumor cell cuproptosis. The production of OH could also trigger the release of XMD8-92 for effectively inhibiting the efferocytosis of macrophages to convert immunosuppressive apoptosis of cancer cells into proinflammatory secondary necrosis. The simultaneous induction of pyroptosis, cuproptosis, and secondary necrosis effectively converts the tumor microenvironment from "cold" to "hot" conditions, making it an effective antigen pool. This transformation successfully activates the antitumor immune response, inhibiting tumor growth and metastasis. 10.1021/acsnano.4c01518
Peptide-Driven Proton Sponge Nano-Assembly for Imaging and Triggering Lysosome-Regulated Immunogenic Cancer Cell Death. Advanced materials (Deerfield Beach, Fla.) Triggering lysosome-regulated immunogenic cell death (ICD, e.g., pyroptosis and necroptosis) with nanomedicines is an emerging approach for turning an "immune-cold" tumor "hot"-a key challenge faced by cancer immunotherapies. Proton sponge such as high-molecular-weight branched polyethylenimine (PEI) is excellent at rupturing lysosomes, but its therapeutic application is hindered by uncontrollable toxicity due to fixed charge density and poor understanding of resulted cell death mechanism. Here, a series of proton sponge nano-assemblies (PSNAs) with self-assembly controllable surface charge density and cell cytotoxicity are created. Such PSNAs are constructed via low-molecular-weight branched PEI covalently bound to self-assembling peptides carrying tetraphenylethene pyridinium (PyTPE, an aggregation-induced emission-based luminogen). Assembly of PEI assisted by the self-assembling peptide-PyTPE leads to enhanced surface positive charges and cell cytotoxicity of PSNA. The self-assembly tendency of PSNAs is further optimized by tuning hydrophilic and hydrophobic components within the peptide, thus resulting in the PSNA with the highest fluorescence, positive surface charge density, cell uptake, and cancer cell cytotoxicity. Systematic cell death mechanistic studies reveal that the lysosome rupturing-regulated pyroptosis and necroptosis are at least two causes of cell death. Tumor cells undergoing PSNA-triggered ICD activate immune cells, suggesting the great potential of PSNAs to trigger anticancer immunity. 10.1002/adma.202307679
Single-walled carbon-nanohorns improve biocompatibility over nanotubes by triggering less protein-initiated pyroptosis and apoptosis in macrophages. He Bing,Shi Yujie,Liang Yanqin,Yang Anpu,Fan Zhipu,Yuan Lan,Zou Xiajuan,Chang Xin,Zhang Hua,Wang Xueqing,Dai Wenbin,Wang Yiguang,Zhang Qiang Nature communications Single-walled carbon-nanohorns (SNH) exhibit huge application prospects. Notably, spherical SNH possess different morphology from conventional carbon nanotubes (CNT). However, there is a tremendous lack of studies on the nanotoxicity and mechanism of SNH, and their comparison with nanotubes. Here, the dissimilarity between SNH and CNT is found in many aspects including necrosis, pyroptosis, apoptosis, protein expression, hydrolases leakage, lysosome stress, membrane disturbance and the interaction with membrane proteins. The improved biocompatibility of SNH over four types of established CNT is clearly demonstrated in macrophages. Importantly, a key transmembrane protein, glycoprotein nonmetastatic melanoma protein B (GPNMB) is discovered to initiate the nanotoxicity. Compared to CNT, the weaker nano-GPNMB interaction in SNH group induces lower degree of cascade actions from nano/membrane interplay to final cell hypotoxicity. In conclusion, the geometry of single-construct unit, but not that of dispersive forms or intracellular levels of nanocarbons make the most difference. 10.1038/s41467-018-04700-z
A cooperative nano-CRISPR scaffold potentiates immunotherapy via activation of tumour-intrinsic pyroptosis. Nature communications Efficient cancer immunotherapy depends on selective targeting of high bioactivity therapeutic agents to the tumours. However, delivering exogenous medication might prove difficult in clinical practice. Here we report a cooperative Nano-CRISPR scaffold (Nano-CD) that utilizes a specific sgRNA, selected from a functional screen for triggering endogenous GDSME expression, while releasing cisplatin to initiate immunologic cell death. Mechanistically, cascade-amplification of the antitumor immune response is prompted by the adjuvantic properties of the lytic intracellular content and enhanced by the heightened GDSME expression, resulting in pyroptosis and the release of tumor associated antigens. Neither of the single components provide efficient tumour control, while tumor growth is efficiently inhibited in primary and recurrent melanomas due to the combinatorial effect of cisplatin and self-supplied GSDME. Moreover, Nano-CD in combination with checkpoint blockade creates durable immune memory and strong systemic anti-tumor immune response, leading to disease relapse prevention, lung metastasis inhibition and increased survival in mouse melanomas. Taken together, our therapeutic approach utilizes CRISPR-technology to enable cell-intrinsic protein expression for immunotherapy, using GDSME as prototypic immune modulator. This nanoplatform thus can be applied to modulate further immunological processes for therapeutic benefit. 10.1038/s41467-023-36550-9
Radiofrequency-Activated Pyroptosis of Bi-Valent Gold Nanocluster for Cancer Immunotherapy. ACS nano Pyroptosis is gasdermin-mediated programmed necrosis that exhibits promising potential application in cancer immunotherapy, and the main challenge lies in how to provoke specific pyroptosis of tumor cells. Here, GC@PNA with a precisely stoichiometric ratio of Au(I) ion/Au(0) atom induced pyroptosis of tumor cells by its radiofrequency (RF)-heating effect. An / assay on 4T1 tumor cells indicates RF-activated pyroptosis of tumor cells elicits a robust ICD effect, enhancing the synergistic antitumor efficacy of GC@PNA with decitabine, significantly suppressing tumor metastasis and relapse by provoking systemic antitumor immune responses. Utilizing RF-activated pyroptotic immune responses, GC@PNA efficiently enhances the antitumor efficacy of αPD-1 immunotherapy under RF irradiation and provides a promising strategy for improving cancer immunotherapy by the noninvasive RF field with high clinical transformation potential. 10.1021/acsnano.2c09242
A Mild Hyperthermia Hollow Carbon Nanozyme as Pyroptosis Inducer for Boosted Antitumor Immunity. ACS nano The immune checkpoint blockade (ICB) antibody immunotherapy has demonstrated clinical benefits for multiple cancers. However, the efficacy of immunotherapy in tumors is suppressed by deficient tumor immunogenicity and immunosuppressive tumor microenvironments. Pyroptosis, a form of programmed cell death, can release tumor antigens, activate effective tumor immunogenicity, and improve the efficiency of ICB, but efficient pyroptosis for tumor treatment is currently limited. Herein, we show a mild hyperthermia-enhanced pyroptosis-mediated immunotherapy based on hollow carbon nanozyme, which can specifically amplify oxidative stress-triggered pyroptosis and synchronously magnify pyroptosis-mediated anticancer responses in the tumor microenvironment. The hollow carbon sphere modified with iron and copper atoms (HCS-FeCu) with multiple enzyme-mimicking activities has been engineered to induce cell pyroptosis via the radical oxygen species (ROS)-Tom20-Bax-Caspase 3-gasdermin E (GSDME) signaling pathway under light activation. Both and antineoplastic results confirm the superiority of HCS-FeCu nanozyme-induced pyroptosis. Moreover, the mild photothermal-activated pyroptosis combining anti-PD-1 can enhance antitumor immunotherapy. Theoretical calculations further indicate that the mild photothermal stimulation generates high-energy electrons and enhances the interaction between the HCS-FeCu surface and adsorbed oxygen, facilitating molecular oxygen activation, which improves the ROS production efficiency. This work presents an approach that effectively transforms immunologically "cold" tumors into "hot" ones, with significant implications for clinical immunotherapy. 10.1021/acsnano.3c07601
Cell Death Mediated by the Pyroptosis Pathway with the Aid of Nanotechnology: Prospects for Cancer Therapy. Wu Dan,Wang Sheng,Yu Guocan,Chen Xiaoyuan Angewandte Chemie (International ed. in English) Pyroptosis, a unique form of programmed cell death (PCD) that is characterized by DNA fragmentation, chromatin condensation, cellular swelling with big bubbles, and leakage of cell content, has been proven to have a close relationship with human diseases, such as inflammatory diseases and malignant tumors. Since a new gasdermin-D (GSDMD) protein was identified in 2015, various strategies have been developed to induce pyroptosis for cancer therapy, including ions, small-molecule drugs and nanomaterials. Although there are a number of reviews about the close relationship between the pyroptosis mechanism and the occurrence of various cancers, a summary covering recent progress in the field of nanomedicines in pyroptosis-based cancer therapy has not yet been presented. Therefore, it is urgent to fill this gap and light up future directions for the use of this powerful tool to combat cancer. In this Minireview, recent progress in cancer treatment based on pyroptosis induced by nanoparticles will be described in detail, the design highlights and the therapeutic advantages are emphasized, and future perspectives in this emerging area are proposed. 10.1002/anie.202010281
A Dual-Responsive STAT3 Inhibitor Nanoprodrug Combined with Oncolytic Virus Elicits Synergistic Antitumor Immune Responses by Igniting Pyroptosis. Advanced materials (Deerfield Beach, Fla.) Immune checkpoint blockade (ICB) therapy shows excellent efficacy against malignancies; however, insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (TME) are considered as the two major stumbling blocks to a broad ICB response. Here, a combinational therapeutic strategy is reported, wherein TME-reactive oxygen species/pH dual-responsive signal transducers and activators of transcription 3 inhibitor nanoprodrugs MPNPs are combined with oncolytic herpes simplex virus 1 virotherapy to synergistically ignite pyroptosis for enhancing immunotherapy. MPNPs exhibit a certain level of tumor accumulation, reduce tumor cell stemness, and enhance antitumor immune responses. Furthermore, the simultaneous application of oncolytic viruses (OVs) confers MPNPs with higher tumor penetration capacity and remarkable gasdermin-E-mediated pyroptosis, thereby reshaping the TME and transforming "cold" tumors into "hot" ones. This "fire of immunity" strategy successfully activates robust T-cell-dependent antitumor responses, potentiating ICB effects against local recurrence and pulmonary metastasis in preclinical "cold" murine triple-negative breast cancer and syngeneic oral cancer models. Collectively, this work may pave a new way and offer an unprecedented opportunity for the combination of OVs with nanomedicine for cancer immunotherapy. 10.1002/adma.202209379
Nanodrug Augmenting Antitumor Immunity for Enhanced TNBC Therapy via Pyroptosis and cGAS-STING Activation. Nano letters Pyroptosis is a proinflammatory form of programmed cell death that results in the release of cellular contents and activation of immune responses. However, GSDME (a pyroptosis-executed protein) is suppressed in many cancers. Herein, we constructed a nanoliposome (GM@LR) for codelivering the GSDME-expressing plasmid and manganese carbonyl (MnCO) into TNBC cells. MnCO generated Mn and carbon monoxide (CO) in the presence of HO. The CO-activated caspase-3, which cleaved the expressed GSDME, converting apoptosis to pyroptosis in 4T1 cells. In addition, Mn promoted maturation of dendritic cells (DCs) by the activation of STING signaling pathway. The increased proportion of intratumoral mature DCs brought about massive infiltration of cytotoxic lymphocytes, leading to a robust immune response. Besides, Mn could be applied for magnetic resonance imaging (MRI)-guided metastasis detection. Taken together, our study showed that GM@LR nanodrug could effectively inhibit tumor growth via pyroptosis and STING activation combined immunotherapy. 10.1021/acs.nanolett.3c01008