RESUMEN
The impact of nanoplastics (NPs) on human health is still not well understood, and more research is needed to better understand the risks associated with these particles. In this study, we found that oral administration of polyethylene (PE) NPs in a mice model significantly disrupted the intestinal microenvironment, which shapes adaptive immune response and favors the established in situ colorectal tumor growth. Using single-cell RNA sequencing technology, we show that NPs triggered colon IL-1ß-producing macrophages by inducing lysosome damage, leading to colonic Treg and Th17 differentiation associated with T cell exhaustion, which creates a colon environment that favors the tumor initiation and progress. A similar effect is also observed in polystyrene NPs. Our result provides insight into the potential link between NPs ingestion and colon tumorigenesis, and the urgency of addressing plastic pollution worldwide.
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Colon , Microplásticos , Humanos , Animales , Ratones , Intestinos , Inmunidad Adaptativa , Macrófagos , PoliestirenosRESUMEN
Myeloid-derived suppressor cells (MDSCs) are recognized as major immune suppressor cells in the tumor microenvironment that may inhibit immune checkpoint blockade (ICB) therapy. Here, we developed a Stattic-loaded mesoporous silica nanoparticle (PEG-MSN-Stattic) delivery system to tumor sites to reduce the number of MDSCs in tumors. This approach is able to significantly deplete intratumoral MSDCs and thereby increase the infiltration of T lymphocytes in tumors to enhance ICB therapy. Our approach may provide a drug delivery strategy for regulating the tumor microenvironment and enhancing cancer immunotherapy efficacy.
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Inmunoterapia , Células Supresoras de Origen Mieloide , Nanopartículas , Dióxido de Silicio , Microambiente Tumoral , Dióxido de Silicio/química , Nanopartículas/química , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Inmunoterapia/métodos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Animales , Ratones , Porosidad , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Polietilenglicoles/químicaRESUMEN
BACKGROUND AIMS: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has shown great success in clinical trials. Programmed cell death 1 (PD-1)-expressing TILs show high specificity to autologous tumor cells. However, limited therapeutic efficiency is observed as a result of the tumor immune microenvironment (TIME). METHODS: Coupling PD-1+ex vivo-derived TILs with a monoclonal antibody against anti-PD-1 (aPD-1) reinvigorated the anti-tumor response of TILs against solid tumor without altering their high tumor targeting ability. RESULTS: Using a melanoma-bearing mouse model, PD-1+ TILs blocked with aPD-1 (PD-1+ TILs-aPD-1) exhibited a high capability for tumor targeting as well as improved anti-tumor response in TIME. Tumor growth was substantially delayed in the mice treated with PD-1+ TILs-aPD-1. CONCLUSIONS: The strategy utilizing TIL therapy coupled with immune checkpoint antibodies may extend to other therapeutic targets of ACT.
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Inmunoterapia Adoptiva , Linfocitos Infiltrantes de Tumor , Receptor de Muerte Celular Programada 1 , Animales , Apoptosis , Linfocitos T CD8-positivos , Tratamiento Basado en Trasplante de Células y Tejidos , Ratones , Receptor de Muerte Celular Programada 1/metabolismo , Microambiente TumoralRESUMEN
The acidic tumor microenvironment (TME) is unfriendly to the activity and function of immune cells in the TME. Here, we report inorganic nanozymes (i.e., SnSe NSs) that mimic the catalytic activity of lactate dehydrogenase to degrade lactate to pyruvate, contributing to the metabolic treatment of tumors. As found in this study, SnSe NSs successfully decreased lactate levels in cells and tumors, as well as reduced tumor acidity. This is associated with activation of the immune response of T cells, thus alleviating the immunosuppressive environment of the TME. More importantly, the nanozyme successfully inhibited tumor growth in mutilate mouse tumor models. Thus, SnSe NSs show a promising result in lactate depletion and tumor suppression, which exemplifies its potential strategy in targeting lactate for metabolic therapy.
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Neoplasias , Microambiente Tumoral , Ratones , Animales , L-Lactato Deshidrogenasa/metabolismo , Neoplasias/metabolismo , Ácido Láctico/metabolismo , ÁcidosRESUMEN
Introducing specific strains of probiotics into the gut microbiome is a promising way to modulate the intestinal microbiome to treat various health conditions clinically. However, oral probiotics typically have a temporary or limited impact on the gut microbiome and overall health benefits. Here, we reported a 3D printed cellulose-derived spiral tube-like scaffold that enabled high efficacy of the oral delivery of probiotics. Benefiting from the unique surface pattern, this system can effectively extend the retention time of loaded probiotics in the gut without invading nearby tissues, provide a favorable environment for the survival and long-term colonization of loaded probiotics, and influence the intestinal ecosystem as a dietary fiber after degradation. We demonstrate Roseburia intestinalis-loaded scaffold exerts noticeable impacts on the regulation of the gut microbiome to treat various gut-related diseases, including obesity and inflammatory bowel disease; thus, we provide a universal platform for oral delivery of probiotics.
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Celulosa , Microbioma Gastrointestinal , Impresión Tridimensional , Probióticos , Probióticos/administración & dosificación , Celulosa/química , Administración Oral , Animales , Ratones , Humanos , Andamios del Tejido/químicaRESUMEN
Gamma-delta (γδ) T cell-based cancer immunotherapies represent a promising avenue for cancer treatment. However, their development is challenged by the limited expansion and differentiation of the cells ex vivo. Here we induced the endogenous expansion and activation of γδ T cells through oral administration of garlic-derived nanoparticles (GNPs). We found that GNPs could significantly promote the proliferation and activation of endogenous γδ T cells in the intestine, leading to generation of large amount of interferon-γ (IFNγ). Moreover GNP-treated mice showed increased levels of chemokine CXCR3 in intestinal γδ T cells, which can drive their migration from the gut to the tumour environment. The translocation of γδ T cells and IFNγ from the intestine to extraintestinal subcutaneous tumours remodels the tumour immune microenvironment and synergizes with anti-PD-L1, inducing robust antitumour immunity. Our study delineates mechanistic insight into the complex gut-tumour interactome and provides an alternative approach for γδ T cell-based immunotherapy.
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How to promote wound healing is still a major challenge in the healthcare while macrophages are a critical component of the healing process. Compared to various bioactive drugs, many plants have been reported to facilitate the wound healing process by regulating the immune response of wounds. In this work, a Three-dimensional (3D) printed hydrogel scaffold loaded with natural Centella asiatica extract (CA extract) is developed for wound healing. This CA@3D scaffold uses gelatin (Gel) and sodium alginate (SA) with CA extract as bio-ink for 3D printing. The CA extract contains a variety of bioactive compounds that make the various active ingredients in Centella asiatica work in concert. The printed CA@3D scaffold can fit the shape of wound, orchestrate the macrophages and immune responses within the wound, and promote wound healing compared to commercial wound dressings. The underlying mechanism of promoting wound healing is also illuminated by applying multi-omic analyses. Moreover, the CA extract loaded 3D scaffold also showed great ability to promote wound healing in diabetic chronic wounds. Due to its ease of preparation, low-cost, biosafety, and therapeutic outcomes, this work proposes an effective strategy for promoting chronic wound healing.
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Hidrogeles , Plantas Medicinales , Hidrogeles/farmacología , Cicatrización de Heridas , Extractos Vegetales/farmacología , Alginatos/farmacologíaRESUMEN
Reactive oxygen species (ROS) are crucial signaling molecules that can arouse immune system. In recent decades, ROS has emerged as a unique therapeutic strategy for malignant tumors as (i) it can not only directly reduce tumor burden but also trigger immune responses by inducing immunogenic cell death (ICD); and (ii) it can be facilely generated and modulated by radiotherapy, photodynamic therapy, sonodynamic therapy and chemodynamic therapy. The anti-tumor immune responses are, however, mostly downplayed by the immunosuppressive signals and dysfunction of effector immune cells within the tumor microenvironment (TME). The past years have seen fierce developments of various strategies to power ROS-based cancer immunotherapy by e.g. combining with immune checkpoints inhibitors, tumor vaccines, and/or immunoadjuvants, which have shown to potently inhibit primary tumors, metastatic tumors, and tumor relapse with limited immune-related adverse events (irAEs). In this review, we introduce the concept of ROS-powered cancer immunotherapy, highlight the innovative strategies to boost ROS-based cancer immunotherapy, and discuss the challenges in terms of clinical translation and future perspectives.
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Vacunas contra el Cáncer , Neoplasias , Fotoquimioterapia , Humanos , Especies Reactivas de Oxígeno , Inmunoterapia , Adyuvantes Inmunológicos , Microambiente Tumoral , Neoplasias/terapia , Línea Celular TumoralRESUMEN
Acute respiratory distress syndrome (ARDS) is a severe lung condition with a high mortality rate and a lack of effective drug therapy. In this work, we developed mesenchymal stem cell (MSC)-derived extracellular vesicles with high PD-L1 expression (MSC-EVs-PD-L1) for treating lipopolysaccharide (LPS)-induced pneumonia by intratracheal administration. We found an upregulation of PD-1 expression in the inflammatory region of murine lungs; hence, MSC-EVs-PD-L1 exerted immunosuppressive effects via the PD-1/PD-L1 signaling pathway. Furthermore, we treated LPS-induced pneumonia mice by intratracheal administration, which enabled heavy drug accumulation in the lungs of mice and better therapeutic efficacy compared to systemic administration. Our results suggest that MSC-EVs-PD-L1 has the potential to provide a universal platform technology for the immunotherapy of pneumonia.
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Vesículas Extracelulares , Neumonía , Animales , Ratones , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Lipopolisacáridos/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Vesículas Extracelulares/metabolismo , Neumonía/terapia , Neumonía/metabolismoRESUMEN
Tumor vaccines have been showing a relatively weak response rate in cancer patients, while deficiencies in delivery efficiency to dendritic cells (DCs), as well as DC-intrinsic immunosuppressive signals, contribute to a great extent. In this work, we report an implantable blood clot loaded with liposomes-protamine-hyaluronic acid nanoparticles (LPH NPs) containing vaccine (LPH-vaccine) and LPH NPs containing siRNA (LPH-siRNA) for synergistic DC recruitment and activation. The subcutaneously implanted blood clot scaffold can recruit abundant immune cells, particularly DCs, to form a DC-rich environment in vivo. Within the scaffold, LPH-vaccine effectively delivers antigens and adjuvants to the recruited DCs and induces the maturation of DCs. More importantly, LPH-siRNA that targets programmed death-ligand 1 (PD-L1) and T cell immunoglobulin and mucin-containing molecule 3 (TIM-3) can reduce immunosuppressive signals in mature DCs and prevent the DCs from expressing a regulatory program in the scaffold. The activated DCs correlate with an improved magnitude and efficacy of T cell priming, resulting in the production of tumor antigen-specific T cells in multiple mouse models. Our strategy can also be used for patient-tailored therapy by change of tumor neoantigens, suggesting a promising strategy for cancer therapy in the clinic.
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Vacunas contra el Cáncer , Neoplasias , Trombosis , Animales , Ratones , ARN Interferente Pequeño/genética , Liposomas , Antígeno B7-H1/genética , Receptor 2 Celular del Virus de la Hepatitis A , Inmunoterapia/métodos , Neoplasias/terapia , Células DendríticasRESUMEN
Nanoplastics (NPs) as contaminants in food and water have drawn increasing public attention. However, little is known about how NPs shape the gut immune landscape after injection. In this study, we fabricate NPs (â¼500 nm) and microplastics (MPs) (â¼2 µm) and evaluate their in vivo effects by feeding them to mice. The results suggest that NPs show a better ability to induce gut macrophage activation than MPs. In addition, NPs trigger gut interleukin-1 (IL-1)-producing macrophage reprogramming via inducing lysosomal damage. More importantly, IL-1 signaling from the intestine can affect brain immunity, leading to microglial activation and Th17 differentiation, all of which correlates with a decline in cognitive and short-term memory in NP-fed mice. Thus, this study provides insight into the mechanism of action of the gut-brain axis, delineates the way NPs reduce brain function, and highlights the importance of fixing the plastic pollution problem worldwide.
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Interleucina-1 , Microplásticos , Animales , Ratones , Microplásticos/toxicidad , Plásticos , Macrófagos , Encéfalo , IntestinosRESUMEN
Severe pneumonia may induce sequelae and accelerated aging process even after the person has recovered. However, the underline mechanism is not very clear. More research is needed to fully understand the long-term effects of severe pneumonia. In this study, we found that mice recovered from severe pneumonia showed lung immunosenescence, which was characterized by a bias naive-memory balance of T lymphocytes in the lung. The reduction of naïve T cells is associated with the diminished immune response to cancer or external new antigens, which is one of the key changes that occurs with age. Our results also indicate the link between severe pneumonia and aging process, which is mediated by the disrupted T cells homeostasis in the lungs after pneumonia.
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Inmunosenescencia , Neumonía , Animales , Ratones , Linfocitos T CD8-positivos , Progresión de la Enfermedad , Pulmón , EnvejecimientoRESUMEN
Advances in the development of therapeutic extracellular vesicles (EVs) for cancer immunotherapy have allowed them to emerge as an alternative to cell therapy. In this proof-of-concept work, we develop bispecific EVs (BsEVs) by genetically engineering EV-producing dendritic cells (DCs) with aCD19 scFv and PD1 for targeting tumor antigens and blocking immune checkpoint proteins simultaneously. We find that these bispecific EVs (EVs-PD1-aCD19) have an impressive ability to accumulate in huCD19-expressing solid tumors following intravenous injection. In addition, EVs-PD1-aCD19 can remarkably reverse the immune landscape of the solid tumor by blocking PD-L1. Furthermore, EVs-PD1-aCD19 can also target tumor-derived EVs in circulation, which prevents the formation of a premetastatic niche in other tissues. Our technology is a demonstration of bispecific EV-based cancer immunotherapy, which may inspire treatments against various types of tumors with different surface antigens and even a patient-tailored therapy.
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Vesículas Extracelulares , Neoplasias , Humanos , Vesículas Extracelulares/metabolismo , Neoplasias/terapia , Neoplasias/metabolismo , Antígenos de Neoplasias/metabolismo , Inmunoterapia , Células DendríticasRESUMEN
Neurological disorders are a common feature in patients who recover from severe acute pneumonia. However, the underlying mechanisms remain poorly understood. Here, we show that the neurological syndromes after severe acute pneumonia are partly attributed to the translocation of endogenous bacteria from the lung to the brain during pneumonia. Using principal components analysis, similarities were found between the brain's flora species and those of the lungs, indicating that the bacteria detected in the brain may originate from the lungs. We also observed impairment of both the lung-blood and brain-blood barriers, allowing endogenous lung bacteria to invade the brain during pneumonia. An elevated microglia and astrocyte activation signature via bacterial infection-related pathways was observed, indicating a bacterial-induced disruption of brain homeostasis. Collectively, we identify endogenous lung bacteria that play a role in altering brain homeostasis, which provides insight into the mechanism of neurological syndromes after severe pneumonia.
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Bacterias , Encéfalo , Pulmón , Enfermedades del Sistema Nervioso , Neumonía , Humanos , Encéfalo/microbiología , Pulmón/microbiología , Enfermedades del Sistema Nervioso/complicaciones , Neumonía/etiologíaRESUMEN
Immunotherapy is used to regulate systemic hyperactivation or hypoactivation to treat various diseases. Biomaterial-based immunotherapy systems can improve therapeutic effects through targeted drug delivery, immunoengineering, etc. However, the immunomodulatory effects of biomaterials themselves cannot be neglected. In this review, we outline biomaterials with immunomodulatory functions discovered in recent years and their applications in disease treatment. These biomaterials can treat inflammation, tumors, or autoimmune diseases by regulating immune cell function, exerting enzyme-like activity, neutralizing cytokines, etc. The prospects and challenges of biomaterial-based modulation of immunotherapy are also discussed.
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Implanted biomaterials have transformed healthcare and the treatment of injury and disease, but their influence on the local immune landscape remains unclear. Here we discovered that degradation-resistant titanium-based implants establish an immunosuppressive microenvironment by recruiting myeloid cells, including monocytes, macrophages, neutrophils, and myeloid-lineage dendritic cells. Unlike normal tissues, the tissues nearby implants exhibit an chronic inflamed and immunosuppressive status characterised by myeloid-rich, T cell-exhaustion gene signature by single-cell RNA sequencing. Vitamin C treatment provides an effective strategy to rescue the immunosuppressive microenvironment, which can be used as a regular supplement to reduce the risk of malignant cell survival around the implants.
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Autoimmune diseases are the third most common disease influencing the quality of life of many patients. Here, a programmed cell death-ligand 1 + (PD-L1) mesenchymal stem cell (MSC) derived extracellular vesicles (MSC-sEVs-PD-L1) using lentivirus-mediated gene transfection technology is developed for reconfiguration of the local immune microenvironment of affected tissue in autoimmune diseases. MSC-sEVs-PD-L1 exhibits an impressive ability to regulate various activated immune cells to an immunosuppressed state in vitro. More importantly, in dextran sulfate sodium-induced ulcerative colitis (UC) and imiquimod-induced psoriasis mouse models, a significantly high accumulation of MSC-sEVs-PD-L1 is observed in the inflamed tissues compared to the PD-L1+ MSCs. Therapeutic efficiency in both UC and psoriasis mouse disease models is demonstrated using MSC-sEVs-PD-L1 to reshape the inflammatory ecosystem in the local immune context. A technology is developed using MSC-sEVs-PD-L1 as a natural delivery platform for autoimmune diseases treatment with high clinical potential.
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Enfermedades Autoinmunes , Vesículas Extracelulares , Células Madre Mesenquimatosas , Animales , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/terapia , Antígeno B7-H1/genética , Ecosistema , Vesículas Extracelulares/metabolismo , Humanos , Células Madre Mesenquimatosas/metabolismo , Ratones , Calidad de VidaRESUMEN
Owing to the immune microenvironment of bones and low selectivity of the drug, patients with bone metastases often respond poorly to immunotherapy. In this study, programmed cell death protein 1 (PD1)-expressing hematopoietic stem cells (HSCs) are genetically engineered for bone-targeted delivery of the transforming growth factor beta (TGF-ß) small-molecule inhibitor SB-505124 (SB@HSCs-PD-1). Intriguingly, compared to anti-PD-L1 monoclonal antibodies, as "living drugs", HSCs-PD-1 not only show great targeting ability to the bone marrow, but are also able to reduplicate themselves within the bone marrow niche and continuously express PD-1 molecules. The SB released from HSCs-PD-1 competitively bound to TGF-ß receptors on CD4+ T cells and facilitate CD4+ T cell differentiation to helper T (TH )1 and TH 2 cells, thereby reprogramming the local immunosuppressive milieu of the bone marrow. Additionally, HSCs-PD-1 can block programmed death-ligand 1 on tumor and myeloid cells, resulting in reinvigorated anti-tumor immunity of T cells. In conclusion, in the present study, an alternative cell engineering strategy is delineated for immune checkpoint blockade therapy, to target bone metastasis using HSCs as a platform, which shows great promise in the treatment of bone metastases.
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Neoplasias Óseas , Receptor de Muerte Celular Programada 1 , Anticuerpos Monoclonales/farmacología , Neoplasias Óseas/terapia , Células Madre Hematopoyéticas/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia/métodos , Receptores de Factores de Crecimiento Transformadores beta , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Microambiente TumoralRESUMEN
Mitochondrial dysfunction is a fundamental pathological feature of Alzheimer's disease (AD). However, toxicity and poor brain enrichment of existing mitophagy inducers limit their further applications. In this study, a platform for AD therapy is developed using nanosized mesenchymal-stem-cells-derived extracellular vesicles with tyrosine phosphatase-2 (SHP2) high-expression (MSC-EVs-SHP2). The high blood-brain barrier penetration ability of MSC-EVs-SHP2 is demonstrated in AD-mice, facilitating SHP2 delivery to the brain. In addition, MSC-EVs-SHP2 significantly induces mitophagy of neuronal cells, which alleviates mitochondrial damage-mediated apoptosis and NLRP3 inflammasome activation. Mitophagy further diminishes neuronal cells apoptosis and neuroinflammation, culminating with rescued synaptic loss and cognitive decline in an AD mouse model. The EV-engineering technology provides a potential platform for effective AD therapy by inducing mitophagy.
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Enfermedad de Alzheimer , Vesículas Extracelulares , Animales , Ratones , Enfermedad de Alzheimer/terapiaRESUMEN
Pneumonia has contributed to significant mortality owing to the irreversible injury to the lungs and severe inflammation of the tissue. Dexamethasone (DEX) is regarded as an effective drug to relieve the level of pneumonia, while the adverse effect of which is non-negligible. Here, we developed a targeted delivery strategy based on platelet-derived extracellular vesicles (PEVs), which are naturally occurring nanoparticles released by platelets, for DEX delivery in acute pneumonia, aiming to reduce the side effects and improve the therapeutic efficacy. Our strategy may shed light on the problems in DEX-based acute pneumonia therapy clinically.