Universal STING mimic boosts antitumour immunity via preferential activation of tumour control signalling pathways.

The efficacy of STING (stimulator of interferon genes) agonists is due to various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours, and a complex balance between tumour control and progression. Here we report a universal STING mimic (uniSTING) based on a polymeric architecture. UniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNPs) results in potent antitumour efficacy across established and advanced metastatic tumour models, including triple-negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2'3'-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the proinflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen-specific CD8+ T-cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitize dendritic cells via exosome-containing miRNAs that reduced the immunosuppressive Wnt2b, and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibits tumour growth and prolongs animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.

Experimental Realization of Geometry-Dependent Skin Effect in a Reciprocal Two-Dimensional Lattice.

Recent studies of non-Hermitian periodic lattices unveiled the non-Hermitian skin effect (NHSE), in which the bulk modes under the periodic boundary conditions (PBC) become skin modes under open boundary conditions. The NHSE is a topological effect owing to the nontrivial spectral winding, and such spectral behaviors appear naturally in nonreciprocal systems. Hence prevailing approaches rely on nonreciprocity to achieve the NHSE. Here, we report the experimental realization of the geometry-dependent skin effect in a two-dimensional reciprocal system, in which the skin effect occurs only at boundaries whose macroscopic symmetry mismatches with the lattice symmetry. The role of spectral reciprocity and symmetry is revealed by connecting reflective channels at given boundaries with the spectral topology of the PBC spectrum. Our work highlights the vital role of reciprocity, symmetry, and macroscopic geometry on the NHSE in dimensionality larger than one and opens new routes for wave structuring using non-Hermitian effects.

Lipid Mediators Metabolic Chaos of Asthmatic Mice Reversed by Rosmarinic Acid.

BACKGROUND AND OBJECTIVE: Asthma is a common chronic inflammatory disease of the airways with no known cure. Lipid mediators (LMs) are a kind of inflammatory signaling molecules which are believed to be involved in the development of asthma. Hyssopus cuspidatus Boriss. is a traditional Uyghur medicine, which is widely used in the treatment of asthma and other respiratory diseases. Extraction of Hyssopus cuspidatus Boriss. was reported to neutralize asthma symptoms. The purpose of the study was to investigate both the anti-inflammatory and immunoregulation properties of the Hyssopus cuspidatus Boriss. extract (SXCF) and its main active constituent, rosmarinic acid (RosA), in vivo. The effect of RosA, a major constituent of SXCF, was evaluated on an asthmatic model, with both anti-inflammatory and immunoregulation properties. MATERIALS AND METHODS: Anti-inflammatory effect of SXCF and RosA was assessed using OVA-induced asthma model mice by UPLC-MS/MS method. RESULTS: Overall, RosA played a critical role in anti-asthma treatment. In total, 90% of LMs species that were significantly regulated by SXCF were covered. On the most important LMs associated with asthma, RosA equivalent induced similar effects as SXCF did. It is believed that some constituents in SXCF could neutralize RosA excessive impacts on LMs.

Integration of network pharmacology, transcriptomics and molecular docking reveals two novel hypoglycemic components in snow chrysanthemum.

Our previous studies uncovered the glucose-lowering properties of snow chrysanthemum tea, however, the active ingredients and underlying mechanisms were yet to be uncovered. Flavonoids are the most active and abundant components in snow chrysanthemum tea. In this study, we treated leptin-deficient diabetic ob/ob or high-fat diet (HFD)-induced C57BL/6 J obese mice with or without total flavonoids of snow chrysanthemum (TFSC) for 14 weeks. Results indicated that TFSC ameliorated dyslipidemia and fatty liver, thereby reducing hyperlipidemia. Further mechanism experiments, including RNA-seq and experimental validation, revealed TFSC improved glycolipid metabolism primarily by activating the AMPK/Sirt1/PPARγ pathway. Additionally, by integrating UPLC, network pharmacology, transcriptomics, and experimental validation, we identified two novel hypoglycemic compounds, sulfuretin and leptosidin, in TFSC. Treatment with 12.5 µmol/L sulfuretin obviously stimulated cellular glucose consumption, and sulfuretin (3.125, 6.25 and 12.5 µmol/L) significantly mitigated glucose uptake damage and reliably facilitated glucose consumption in insulin-resistant HepG2 cells. Remarkably, sulfuretin interacted with the ligand-binding pocket of PPARγ via three hydrogen bond interactions with the residues LYS-367, GLN-286 and TYR-477. Furthermore, a concentration of 12.5 µmol/L sulfuretin effectively upregulated the expression of PPARγ, exhibiting a comparable potency to a renowned PPARγ agonist at 20 µmol/L. Taken together, our findings have identified two new hypoglycemic compounds and revealed their mechanisms, which significantly expands people's understanding of the active components in snow chrysanthemum that have hypoglycemic effects.

Tumor-derived nanoseeds condition the soil for metastatic organotropism.

Primary tumors secrete a variety of factors to turn distant microenvironments into favorable and fertile 'soil' for subsequent metastases. Among these 'seeding' factors that initiate pre-metastatic niche (PMN) formation, tumor-derived extracellular vesicles (EVs) are of particular interest as tumor EVs can direct organotropism depending on their surface integrin profiles. In addition, EVs also contain versatile, bioactive cargo, which include proteins, metabolites, lipids, RNA, and DNA fragments. The cargo incorporated into EVs is collectively shed from cancer cells and cancer-associated stromal cells. Increased understanding of how tumor EVs promote PMN establishment and detection of EVs in bodily fluids highlight how tumor EVs could serve as potential diagnostic and prognostic biomarkers, as well as provide a therapeutic target for metastasis prevention. This review focuses on tumor-derived EVs and how they direct organotropism and subsequently modulate stromal and immune microenvironments at distal sites to facilitate PMN formation. We also outline the progress made thus far towards clinical applications of tumor EVs.

Tumour extracellular vesicles and particles induce liver metabolic dysfunction.

Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

Fibrotic immune microenvironment remodeling mediates superior anti-tumor efficacy of a nano-PD-L1 trap in hepatocellular carcinoma.

The local microenvironment where tumors develop can shape cancer progression and therapeutic outcome. Emerging evidence demonstrate that the efficacy of immune-checkpoint blockade (ICB) is undermined by fibrotic tumor microenvironment (TME). The majority of hepatocellular carcinoma (HCC) develops in liver fibrosis, in which the stromal and immune components may form a barricade against immunotherapy. Here, we report that nanodelivery of a programmed death-ligand 1 (PD-L1) trap gene exerts superior efficacy in treating fibrosis-associated HCC when compared with the conventional monoclonal antibody (mAb). In two fibrosis-associated HCC models induced by carbon tetrachloride and a high-fat, high-carbohydrate diet, the PD-L1 trap induced significantly larger tumor regression than mAb with no evidence of toxicity. Mechanistic studies revealed that PD-L1 trap, but not mAb, consistently reduced the M2 macrophage proportion in the fibrotic liver microenvironment and promoted cytotoxic interferon gamma (IFNγ)+tumor necrosis factor α (TNF-α)+CD8+T cell infiltration to the tumor. Moreover, PD-L1 trap treatment was associated with decreased tumor-infiltrating polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) accumulation, resulting in an inflamed TME with a high cytotoxic CD8+T cell/PMN-MDSC ratio conductive to anti-tumor immune response. Single-cell RNA sequencing analysis of two clinical cohorts demonstrated preferential PD-L1 expression in M2 macrophages in the fibrotic liver, thus supporting the translational potential of nano-PD-L1 trap for fibrotic HCC treatment.

Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.

The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) fostering cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite also produced by aggressive cancer cells, activates fibroblasts in the TME, which reciprocally secrete IL-6 loaded extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGFß signaling pathways. EV-associated IL-6 functions as a stroma-tumor messenger, activating the JAK/STAT3 and TGFß signaling pathways in tumor cells and promoting pro-aggressive behaviors. Our findings define the role of MMA in CAF activation to drive metastatic reprogramming, unveiling potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.

Strategies targeting tumor immune and stromal microenvironment and their clinical relevance.

The critical role of tumor microenvironment (TME) in tumor initiation and development has been well-recognized after more than a century of studies. Numerous therapeutic approaches targeting TME are rapidly developed including those leveraging nanotechnology, which have been further accelerated since the emergence of immune checkpoint blockade therapies in the past decade. While there are many reviews focusing on TME remodeling therapies via drug delivery and engineering strategies in animal models, state-of-the-art evaluation of clinical development states of TME-targeted therapeutics is rarely found. Here, we illustrate opportunities for integrating nano-delivery system for the development of TME-specific therapeutic regimen, followed by a comprehensive summary of the most up to date approved or clinically evaluated therapeutics targeting cellular and extracellular components within tumor immune and stromal microenvironment, including small molecule and monoclonal antibody drugs as well as nanomedicines. In the end, we also discuss challenges and possible solutions for clinical translation of TME-targeted nanomedicines.

Nanoparticle Delivery of miR-122 Inhibits Colorectal Cancer Liver Metastasis.

Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as miR-122, a liver-specific miRNA that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented colorectal cancer liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8+/CD4+ T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to antitumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA. SIGNIFICANCE: Highly specific and efficient delivery of miRNA to hepatocytes using nanomedicine has therapeutic potential for the prevention and treatment of colorectal cancer liver metastasis.

Causal Discovery in High-dimensional, Multicollinear Datasets.

As the cost of high-throughput genomic sequencing technology declines, its application in clinical research becomes increasingly popular. The collected datasets often contain tens or hundreds of thousands of biological features that need to be mined to extract meaningful information. One area of particular interest is discovering underlying causal mechanisms of disease outcomes. Over the past few decades, causal discovery algorithms have been developed and expanded to infer such relationships. However, these algorithms suffer from the curse of dimensionality and multicollinearity. A recently introduced, non-orthogonal, general empirical Bayes approach to matrix factorization has been demonstrated to successfully infer latent factors with interpretable structures from observed variables. We hypothesize that applying this strategy to causal discovery algorithms can solve both the high dimensionality and collinearity problems, inherent to most biomedical datasets. We evaluate this strategy on simulated data and apply it to two real-world datasets. In a breast cancer dataset, we identified important survival-associated latent factors and biologically meaningful enriched pathways within factors related to important clinical features. In a SARS-CoV-2 dataset, we were able to predict whether a patient (1) had Covid-19 and (2) would enter the ICU. Furthermore, we were able to associate factors with known Covid-19 related biological pathways.

Bioproduction of D-allulose: Properties, applications, purification, and future perspectives.

D-allulose is the C-3 epimer of D-fructose, which rarely exists in nature, and can be biosynthesized from D-fructose by the catalysis of D-psicose 3-epimerase. D-allulose is safe for human consumption and was recently approved by the United States Food and Drug Administration for food applications. It is not only able be used in food and dietary supplements as a low-calorie sweetener, but also modulates a variety of physiological functions. D-allulose has gained increasing attention owing to its excellent properties. This article presents a review of recent progress on the properties, applications, and bioproduction progress of D-allulose.

Double-bowl state in photonic Dirac nodal line semimetal.

The past decade has seen a proliferation of topological materials for both insulators and semimetals in electronic systems and classical waves. Topological semimetals exhibit topologically protected band degeneracies, such as nodal points and nodal lines. Dirac nodal line semimetals (DNLS), which own four-fold line degeneracy, have drawn particular attention. DNLSs have been studied in electronic systems but there is no photonic DNLS. Here in this work, we provide a new mechanism, which is unique for photonic systems to investigate a stringent photonic DNLS. When truncated, the photonic DNLS exhibits double-bowl states (DBS), which comprise two sets of perpendicularly polarized surface states. In sharp contrast to nondegenerate surface states in other photonic systems, here the two sets of surface states are almost degenerate over the whole-spectrum range. The DBS and the bulk Dirac nodal ring (DNR) dispersion along the relevant directions, are experimentally resolved.

mRNA Delivery of a Bispecific Single-Domain Antibody to Polarize Tumor-Associated Macrophages and Synergize Immunotherapy against Liver Malignancies.

Liver malignancies are among the tumor types that are resistant to immune checkpoint inhibition therapy. Tumor-associated macrophages (TAMs) are highly enriched and play a major role in inducing immunosuppression in liver malignancies. Herein, CCL2 and CCL5 are screened as two major chemokines responsible for attracting TAM infiltration and inducing their polarization toward cancer-promoting M2-phenotype. To reverse this immunosuppressive process, an innovative single-domain antibody that bispecifically binds and neutralizes CCL2 and CCL5 (BisCCL2/5i) with high potency and specificity is directly evolved. mRNA encoding BisCCL2/5i is encapsulated in a clinically approved lipid nanoparticle platform, resulting in a liver-homing biomaterial that allows transient yet efficient expression of BisCCL2/5i in the diseased organ in a multiple dosage manner. This BisCCL2/5i mRNA nanoplatform significantly induces the polarization of TAMs toward the antitumoral M1 phenotype and reduces immunosuppression in the tumor microenvironment. The combination of BisCCL2/5i with PD-1 ligand inhibitor (PD-Li) achieves long-term survival in mouse models of primary liver cancer and liver metastasis of colorectal and pancreatic cancers. The work provides an effective bispecific targeting strategy that could broaden the PD-Li therapy to multiple types of malignancies in the human liver.

Relaxin gene delivery modulates macrophages to resolve cancer fibrosis and synergizes with immune checkpoint blockade therapy.

Cancer fibrosis serves as a major therapeutic barrier in desmoplastic tumors. Relaxin (RLN; a systemic hormone) is efficacious to decrease fibrosis, but the in vivo mechanism of action is not clear. Considering the localization of relaxin family peptide receptor type 1 (RXFP1), the receptor for RLN, on macrophages, we hypothesize that macrophages can be modulated by RLN to ameliorate cancer fibrosis. Using KPC mouse model of pancreatic ductal adenocarcinoma (PDAC), here, we report locally expressed RLN with targeted gene delivery induces increased F4/80+CD206+ macrophages originating from Ly6C+ monocytes, promoting fibrosis depletion and cytotoxic T cell infiltration. Moreover, RLN gene delivery synergizes with PD-L1 blockade for tumor inhibition by enhancing T cell-mediated tumor cell killing and macrophage phagocytosis. Collectively, our results reveal previously unidentified insights into the modulation of macrophages to regulate tumor-associated fibrosis, providing a feasible strategy to reverse the immunosuppressive environment and improve the therapeutic outcome of checkpoint immunotherapies.

Correction: The chemopreventive effects of Huangqin-tea against AOM-induced preneoplastic colonic aberrant crypt foci in rats and omics analysis.

Correction for 'The chemopreventive effects of Huangqin-tea against AOM-induced preneoplastic colonic aberrant crypt foci in rats and omics analysis' by Jie Shen et al., Food Funct., 2020, 11, 9634-9650, DOI: 10.1039/D0FO01731K.

Hepatic macrophages act as a central hub for relaxin-mediated alleviation of liver fibrosis.

Relaxin is an antifibrotic peptide hormone previously assumed to directly reverse the activation of hepatic stellate cells for liver fibrosis resolution. Using nanoparticle-mediated delivery, here we show that, although relaxin gene therapy reduces liver fibrosis in vivo, in vitro treatment fails to induce quiescence of the activated hepatic stellate cells. We show that hepatic macrophages express the primary relaxin receptor, and that, on relaxin binding, they switch from the profibrogenic to the pro-resolution phenotype. The latter releases exosomes that promote the relaxin-mediated quiescence of activated hepatic stellate cells through miR-30a-5p. Building on these results, we developed lipid nanoparticles that preferentially target activated hepatic stellate cells in the fibrotic liver and encapsulate the relaxin gene and miR-30a-5p mimic. The combinatorial gene therapy achieves synergistic antifibrosis effects in models of mouse liver fibrosis. Collectively, our findings highlight the key role that macrophages play in the relaxin-primed alleviation of liver fibrosis and demonstrate a proof-of-concept approach to devise antifibrotic strategies through the complementary application of nanotechnology and basic science.

Preparation of porous silicate supported micro-nano zero-valent iron from copper slag and used as persulfate activator for removing organic contaminants.

Porous silicate supported micro-nano zero-valent iron (PSi@ZVI) was prepared from copper slag (CS) through carbothermal reduction technology, and used as a persulfate (PS) activator for removing organic contaminants. Results showed that the properties of the activator were greatly affected by the preparation conditions. Calcination for 20 min at 1100 °C with 20% anthracite was considered the optimum preparation condition for degradation of orange G (OG). The removal rate of OG was improved by increasing the dosages of PSi@ZVI or PS and raising the reaction temperature. Moreover, PSi@ZVI exhibited excellent PS activator ability in a wide range of initial pH, good degradation capability for eosin Y, methyl orange, acid fuchsine, and methylene blue. The reusability and safety of PSi@ZVI were verified. Electron paramagnetic resonance and radical quenching tests indicated that sulfate radical (SO4-) was the main active species in the PSi@ZVI/PS system. The X-ray diffraction results indicated that a high calcination temperature (1100 °C) was beneficial to the reduction of iron-bearing minerals to ZVI. Scanning electron microscopy and energy-dispersive spectroscopy results revealed that the formation of porous structure of PSi@ZVI and the generation of nano to micro-sized ZVI particles on the surface of the silicate holes. The X-ray photoelectron spectra showed that ZVI was first convert into Fe(II), which mainly activated PS and generated Fe(III) in the PSi@ZVI/PS system. Furthermore, the intermediates of OG were detected using gas chromatography-mass spectrometry, and the possible degradation pathway of OG was proposed. This study provides a novel approach for reuse of CS as a heterogeneous activator to effectively activate PS.

Celastrol nanoemulsion induces immunogenicity and downregulates PD-L1 to boost abscopal effect in melanoma therapy.

Programmed cell death-ligand 1 (PD-L1)-based immune checkpoint blockade therapy using the anti-PD-L1 antibody is effective for a subset of patients with advanced metastatic melanoma but about half of the patients do not respond to the therapy because of the tumor immunosuppressive microenvironment. Immunogenic cell death (ICD) induced by cytotoxins such as doxorubicin (DOX) allows damaged dying tumor cells to release immunostimulatory danger signals to activate dendritic cells (DCs) and T-cells; however, DOX also makes tumor cells upregulate PD-L1 expression and thus deactivate T-cells via the PD-1/PD-L1 pathway. Herein, we show that celastrol (CEL) induced not only strong ICD but also downregulation of PD-L1 expression of tumor cells. Thus, CEL was able to simultaneously activate DCs and T-cells and interrupt the PD-1/PD-L1 pathway between T-cells and tumor cells. In a bilateral tumor model, intratumorally (i.t.) injected celastrol nanoemulsion retaining a high tumor CEL concentration activated the immune system efficiently, which inhibited both the treated tumor and the distant untreated tumor in the mice (i.e., abscopal effect). Thus, this work demonstrates a new and much cost-effective immunotherapy strategy - chemotherapy-induced immunotherapy against melanoma without the need for expensive immune-checkpoint inhibitors.