Lignin-assisted construction of sub-10 nm supramolecular self-assembly for photothermal immunotherapy and potentiating anti-PD-1 therapy against primary and distant breast tumors

Photothermal therapy(PTT) has brought hope for cancer treatments, with hyperthermiainduced immunogenic cell death(ICD), which is a critical part of therapeutically induced antitumor immune responses. Limited immune stimulation response in PTT is the primary reason for incomplete tumor ablation, therefore demonstrating urgent requirements for ICD amplifier. Herein, a sub-10 nm supramolecular nanoassembly was formed by coassembly of clinically approved aluminum adjuvant and commonly used indocyani...     

Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles(VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin(IL)-12, shorthairpin RNA(sh RNA) targeting programmed death ligand 1(PD-L1), and a dominant-negative form of IL-17 receptor A(dn-IL17RA) as...     

Converting bacteria into autologous tumor vaccine via surface biomineralization of calcium carbonate for enhanced immunotherapy

Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy. However, its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment(ITM). Here, we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate(CaCO₃) biomineralized Salmonella(Sal)as an in-situ cancer vaccine producer and systematical ITM regulator. CaCO₃ can be facilely c...     

Dual-responsive nanovaccine for cytosolic delivery of antigens to boost cellular immune responses and cancer immunotherapy

Cancer vaccine contributing to the success of the treatment and prevention of tumors has attracted a huge attention as a strategy for tumor immunotherapy in recent years.A major challenge of cancer vaccine is to target cytosols of dendritic cells(DCs) in the lymph nodes(LNs) to enhance efficiency of antigen cross-presentation, which elicits high levels of cytotoxic T-lymphocytes to destruct tumor cells. Here, we address this issue by conjugating ovalbumin(OVA) to PEG-PCL using disulfide bond(-ss...     

Therapeutic potential of traditional Chinese medicine for the treatment of NAFLD:A promising drug Potentilla discolor BungeOA

Nonalcoholic fatty liver disease(NAFLD) is characterized by excessive accumulation of hepatic lipids and metabolic stress-induced liver injury.There are currently no approved effective pharmacological treatments for NAFLD.Traditional Chinese medicine(TCM) has been used for centuries to treat patients with chronic liver diseases without clear disease types and mechanisms.More recently,TCM has been shown to have unique advantages in the treatment of NAFLD.We performed a systematic review of the me...     

Glycan targeting nanoparticle for photodynamic immunotherapy of melanoma

Interaction between tumour cells and macrophages enables cancer cells to evade immune detection and clearance by interfering with macrophage phagocytosis. The anti-phagocytic signals regulated by anti-phagocytic proteins are termed "don’t eat me" signals; these signals include sialic acidbinding immunoglobulin-type lectin-10(Siglec-10) and the recently revealed CD24 immune checkpoint(ICP). In this study, we demonstrate that targeting a specific glycan on CD24 exhibits the potential to inhibit IC...     

Activation of PXR causes drug interactions with Paxlovid in transgenic mice

Paxlovid is a nirmatrelvir(NMV) and ritonavir(RTV) co-packaged medication used for the treatment of coronavirus disease 2019(COVID-19). The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster. Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid. By using recombinant human cytochrome P450s(CYPs), we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV me...     

Signal transduction mediated by mitogen-activated protein kinases and apoptisis of tumor cells

Objective To make a review about MAPK and apoptosis of tumor cells.Methods We collected a large number of related experimental papers,and summarized key points.Results mitogen activated protein kinase(MAPK)is one of the four biggest signal transduction systems which contain four subtribes named p38,ERK5,ERK and JNK/SAPK respectively.MAPK pathways constitute numerous modular network that regulates a variety of physiological processes,such as cell growth,roliferation,differentiation,and apoptotic cell death.Specially,the function of induced apoptosis in tumor cells has gradually become main focus.Both in-vitro and ex-vivo findings demonstrated that in apoptotic tumor cells the level of phosphorylation of JNK kinase is significantly improved.That means JNK kinase is activated in these tumor cells.At the same time,contrary to JNK kinase,the activity of ERK kinase is usually weakened.So,for most apoptotic tumor cells,JNK is a positive factor,however,ERK kinases is a negative factor.As for the p38 kinase,which can be activated to outside stimulus,also has the promotion of apoptosis.Importantly,ERK kinase activity is suppressed by JNK/p38 kinase during apoptosis induction.Further study demonstrate that the regulatory mechanisms of MAPK in apoptotic tumor cells are:working on upstream of caspase;starting death receptor channel;activating pro-apoptotic Bcl-2 protein family;changing mitochondrial permeability;participating in Fas/Fasl-mediated apoptosis;enhancing the expression of TNF-a and so on.Conclusions The relationship between MAPK and apoptosis of tumor cells is intimate.It is expected to be a new target for tumor in clinical treatment.     

A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here,we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs), organoids(PDOs), and xenografts(PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PD...     

医学英语学习第二期

阅读材料 Fuel①For The Human Engine② Tour body is like an engine. The food you eat③ is the fuel that keeps your body alive and active④. It gives you energy⑤ for work and play, just as the fuel burned⑥ by an engine enables it to pull a train⑦, hoist⑧ a load or run⑨ machinery⑩. All we ask of a steam or gasoline engine(11) is that(12) it(13) should(14) run(15) smoothly and efficiently(16). wher(17) a part wears out(18), we shut the engine down(19) and repair(20) it; but the human body must keep running(21) for a lifetime, repair-     

Iron-doxorubicin prodrug loaded liposome nanogenerator programs multimodal ferroptosis for efficient cancer therapy

Ferroptosis is a new mode of cell death, which can be induced by Fenton reaction-mediated lipid peroxidation. However, the insufficient H₂O₂ and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent ferroptosis. Herein, a self-supplying lipid peroxide nanoreactor was developed to co-delivery of doxorubicin (DOX), iron and unsaturated lipid for efficient ferroptosis. By leveraging the coordination effect between DOX and Fe³⁺, trisulfide bond-bridged DOX dimeric prodrug was actively loaded into the core of the unsaturated lipids-rich liposome via iron ion gradient method. First, Fe³⁺could react with the overexpressed GSH in tumor cells, inducing the GSH depletion and Fe²⁺generation. Second, the cleavage of trisulfide bond could also consume GSH, and the released DOX induces the generation of H₂O_2, which would react with the generated Fe²⁺in step one to induce efficient Fenton reaction-dependent ferroptosis. Third, the formed Fe³⁺/Fe²⁺ couple could directly catalyze peroxidation of unsaturated lipids to boost Fenton reaction-independent ferroptosis. This iron-prodrug liposome nanoreactor precisely programs multimodal ferroptosis by integrating GSH depletion, ROS generation and lipid peroxidation, providing new sights for efficient cancer therapy.     

Perfluorooctyl bromide nanoemulsions holding MnO2 nanoparticles with dual-modality imaging and glutathione depletion enhanced HIFU-eliciting tumor immunogenic cell death

Tumor-targeted immunotherapy is a remarkable breakthrough, offering the inimitable advantage of specific tumoricidal effects with reduced immune-associated cytotoxicity. However, existing platforms suffer from low efficacy, inability to induce strong immunogenic cell death (ICD), and restrained capacity of transforming immune-deserted tumors into immune-cultivated ones. Here, an innovative platform, perfluorooctyl bromide (PFOB) nanoemulsions holding MnO₂ nanoparticles (MBP), was developed to orchestrate cancer immunotherapy, serving as a theranostic nanoagent for MRI/CT dual-modality imaging and advanced ICD. By simultaneously depleting the GSH and eliciting the ICD effect via high-intensity focused ultrasound (HIFU) therapy, the MBP nanomedicine can regulate the tumor immune microenvironment by inducing maturation of dendritic cells (DCs) and facilitating the activation of CD8⁺ and CD4⁺ T cells. The synergistic GSH depletion and HIFU ablation also amplify the inhibition of tumor growth and lung metastasis. Together, these findings inaugurate a new strategy of tumor-targeted immunotherapy, realizing a novel therapeutics paradigm with great clinical significance.     

A self-guidance biological hybrid drug delivery system driven by anaerobes to inhibit the proliferation and metastasis of colon cancer

Colorectal cancer is often accompanied by multiple organ metastasis. Anaerobic Bifidobacterium Infantis(BI) bacterial can selectively grow in hypoxic colorectal tumor microenvironment(TME), to own the natural advantage of preferentially colorectal tumor targeting. Herein, a self-guidance biological hybrid drug delivery system(BI-ES-Fe Alg/DOX)based on BI was constructed to inhibit the proliferation and metastasis of colon cancer.Results demonstrated that BI-ES-Fe Alg/DOX could overcome physical ...     

Elaborately engineering of a dual-drug co-assembled nanomedicine for boosting immunogenic cell death and enhancing triple negative breast cancer treatment

Pure drug-assembled nanosystem provides a facile and promising solution for simple manufacturing of nanodrugs, whereas a lack of understanding of the underlying assembly mechanism and the inefficient and uncontrollable drug release still limits the development and application of this technology. Here, a simple and practical nanoassembly of DOX and DiR is constructed on basis of their co-assembly characteristics. Multiple interaction forces are found to drive the co-assembly process. Moreover, DOX release from the nanoassembly can be well controlled by the acidic tumor microenvironment and laser irradiation, resulting in favorable delivery efficiency of DiR and DOX in vitro and in vivo. As expected, the nanoassembly with high therapeutic safety completely eradicated the mice triple negative breast cancer cells (4T1) on BALB/c mice, owing to synergistic chemo-photothermal therapy. More interestingly, DiR and DOX synergistically induce immunogenic cell death (ICD) of tumor cells after treatment, enabling the mice to acquire immune memory against tumor growth and recurrence. Such a facile nanoassembly technique provides a novel multimodal cancer treatment platform of chemotherapy/phototherapy/immunotherapy.     

Bioresponsive immune-booster-based prodrug nanogel for cancer immunotherapy

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.     

Chemo-photothermal immunotherapy for eradication of orthotopic tumors and inhibition of metastasis by intratumoral injection of polydopamine versatile hydrogels

Cancer remains one of the leading causes of death globally and metastasis always leads to treatment failure. Here, we develop a versatile hydrogel loading photothermal agents, chemotherapeutics, and immune-adjuvants to eradicate orthotopic tumors and inhibit metastasis by combinational therapy. Hydrogel networks were synthesized via the thiol-Michael addition of polydopamine (PDA) with thiolated hyaluronic acid. PDA acted as a cross-linking agent and endowed the hydrogel with excellent photothermal property. Meanwhile, a chemotherapeutic agent, doxorubicin (DOX), was loaded in the hydrogel via π?π stacking with PDA and an immune-adjuvant, CpG-ODN, was loaded via electrostatic interaction. The release of DOX from the hydrogel was initially slow but accelerated due to near infrared light irradiation. The hydrogels showed remarkably synergistic effect against 4T1 cancer cells and stimulated plenty of cytokines secreting from RAW264.7 cells. Moreover, the hydrogels eradicated orthotopic murine breast cancer xenografts and strongly inhibited metastasis after intratumoral injection and light irradiation. The high anticancer efficiency of this chemo-photothermal immunotherapy resulted from the strong synergistic effect of the versatile hydrogels, including the evoked host immune response. The combinational strategy of chemo-photothermal immunotherapy is promising for highly effective treatment of breast cancer.     

On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition

Cancer immunotherapy has become a promising strategy. However, the effectiveness of immunotherapy is restricted in “cold tumors” characterized with insufficient T cells intratumoral infiltration and failed T cells priming. Herein, an on-demand integrated nano-engager (JOT-Lip) was developed to convert cold tumors to hot via “increased DNA damage and dual immune checkpoint inhibition” strategy. JOT-Lip was engineered by co-loading oxaliplatin (Oxa) and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies (Tim-3 mAb) coupled on the liposomal surface by metalloproteinase-2 (MMP-2)-sensitive linker. JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death (ICD) of Oxa, thus promoting T cells intratumoral infiltration. In addition, JQ1 inhibited PD-1/PD-L1 pathway, achieving dual immune checkpoint inhibition combining with Tim-3 mAb, thus effectively promoting T cells priming. It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns (DAMPs), but also enhanced T cells intratumoral infiltration and promoted T cell priming, which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects. Collectively, our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot, which holds great potential in clinical cancer chemoimmunotherapy.     

A cyclodextrin-based nanoformulation achieves co-delivery of ginsenoside Rg3 and quercetin for chemo-immunotherapy in colorectal cancer

The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer (CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment (TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death (ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3 (Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin (QTN) that elicited reactive oxygen species (ROS). To ameliorate in vivo delivery barriers associated with chemotherapeutic drugs, a folate (FA)-targeted polyethylene glycol (PEG)-modified amphiphilic cyclodextrin nanoparticle (NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation (CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.     

Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator

The use of checkpoint-blockade antibodies is still restricted in several malignancies due to the modest efficacy,despite considerable success in anti-tumor immunotherapy.The poor response of cancer cells to immune destruction is an essential contributor to the failure of checkpoint therapy.We hypothesized that combining checkpoint therapy with natural-product chemosensitizer could enhance immune response.Herein,a targeted diterpenoid derivative was integrated with the checkpoint blockade(anti-CT...     

Self-assembled FeS-based cascade bioreactor with enhanced tumor penetration and synergistic treatments to trigger robust cancer immunotherapy

Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death (ICD) to provoke a robust immune response for metastasis control. Here, a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation, chemodynamic (CDT) and photothermal therapy. Ultrasmall FeS-GOx nanodots were synthesized with glucose oxidase (GOx) as template and induced by paclitaxel (PTX) to form self-assembling FeS-GOx@PTX (FGP) via hydrophobic interaction. After accumulated at tumor sites, FGP disassembles to smaller FeS-GOx for enhanced deep tumor penetration. GOx maintains high enzymatic activity to catalyze glucose with assistant of oxygen to generate hydrogen peroxide (H₂O₂) as starvation therapy. Fenton reaction involving the regenerated H₂O₂ in turn produced more hydroxyl radicals for enhanced CDT. Following near-infrared laser at 808 nm, FGPs displayed pronounced tumor inhibition in vitro and in vivo by the combination therapy. The consequent increased exposure to calreticulin amplified ICD and promoted dendritic cells maturation. In combination with anti-CTLA4 checkpoint blockade, FGP can absolutely eliminate primary tumor and avidly inhibit distant tumors due to the enhanced intratumoral infiltration of cytotoxic T lymphocytes. Our work presents a promising strategy for primary tumor and metastasis inhibition.