Phase and Defect Engineering of MoSe2 Nanosheets for Enhanced NIR-II Photothermal Immunotherapy.

Inducing immunogenic cell death (ICD) during photothermal therapy (PTT) has the potential to effectively trigger photothermal immunotherapy (PTI). However, ICD induced by PTT alone is often limited by inefficient PTT, low immunogenicity of tumor cells, and a dysregulated redox microenvironment. Herein, we develop MoSe2 nanosheets with high-percentage metallic 1T phase and rich exposed active Mo centers through phase and defect engineering of MoSe2 as an effective nanoagent for PTI. The metallic 1T phase in MoSe2 nanosheets endows them with strong PTT performance, and the abundant exposed active Mo centers endow them with high activity for glutathione (GSH) depletion. The MoSe2-mediated high-performance PTT synergizing with efficient GSH depletion facilitates the release of tumor-associated antigens to induce robust ICD, thus significantly enhancing checkpoint blockade immunotherapy and activating systemic immune response in mouse models of colorectal cancer and triple-negative metastatic breast cancer.

Nanoparticles for inducing Gaucher disease-like damage in cancer cells.

Nutrient avidity is one of the most distinctive features of tumours. However, nutrient deprivation has yielded limited clinical benefits. In Gaucher disease, an inherited metabolic disorder, cells produce cholesteryl-glucoside which accumulates in lysosomes and causes cell damage. Here we develop a nanoparticle (AbCholB) to emulate natural-lipoprotein-carried cholesterol and initiate Gaucher disease-like damage in cancer cells. AbCholB is composed of a phenylboronic-acid-modified cholesterol (CholB) and albumin. Cancer cells uptake the nanoparticles into lysosomes, where CholB reacts with glucose and generates a cholesteryl-glucoside-like structure that resists degradation and aggregates into microscale crystals, causing Gaucher disease-like damage in a glucose-dependent manner. In addition, the nutrient-sensing function of mTOR is suppressed. It is observed that normal cells escape severe damage due to their inferior ability to compete for nutrients compared with cancer cells. This work provides a bioinspired strategy to selectively impede the metabolic action of cancer cells by taking advantage of their nutrient avidity.

Chiral coordination polymer nanowires boost radiation-induced in situ tumor vaccination.

Radiation-induced in situ tumor vaccination alone is very weak and insufficient to elicit robust antitumor immune responses. In this work, we address this issue by developing chiral vidarabine monophosphate-gadolinium nanowires (aAGd-NWs) through coordination-driven self-assembly. We elucidate the mechanism of aAGd-NW assembly and characterize their distinct features, which include a negative surface charge, ultrafine topography, and right-handed chirality. Additionally, aAGd-NWs not only enhance X-ray deposition but also inhibit DNA repair, thereby enhancing radiation-induced in situ vaccination. Consequently, the in situ vaccination induced by aAGd-NWs sensitizes radiation enhances CD8+ T-cell-dependent antitumor immunity and synergistically potentiates the efficacy immune checkpoint blockade therapies against both primary and metastatic tumors. The well-established aAGd-NWs exhibit exceptional therapeutic capacity and biocompatibility, offering a promising avenue for the development of radioimmunotherapy approaches.

Biomimetic Nanomedicine Targeting Orchestrated Metabolism Coupled with Regulatory Factors to Disrupt the Metabolic Plasticity of Breast Cancer.

Targeting nutrient metabolism has been proposed as an effective therapeutic strategy to combat breast cancer because of its high nutrient requirements. However, metabolic plasticity enables breast cancer cells to survive under unfavorable starvation conditions. The key mammalian target regulators rapamycin (mTOR) and hypoxia-inducible-factor-1 (HIF-1) tightly link the dynamic metabolism of glutamine and glucose to maintain nutrient flux. Blocking nutrient flow also induces autophagy to recycle nutrients in the autophagosome, which exacerbates metastasis and tumor progression. Compared to other common cancers, breast cancer is even more dependent on mTOR and HIF-1 to orchestrate the metabolic network. Therefore, we develop a cascade-boosting integrated nanomedicine to reprogram complementary metabolism coupled with regulators in breast cancer. Glucose oxidase efficiently consumes glucose, while the delivery of rapamycin inside limits the metabolic flux of glutamine and uncouples the feedback regulation of mTOR and HIF-1. The hydroxyl radical generated in a cascade blocks the later phase of autophagy without nutrient recycling. This nanomedicine targeting orchestrated metabolism can disrupt the coordination of glucose, amino acids, nucleotides, lipids, and other metabolic pathways in breast cancer tissues, effectively improving the durable antitumor effect and prognosis of breast cancer. Overall, the cascade-boosting integrated system provides a viable strategy to address cellular plasticity and efficient enzyme delivery.

Combining High-Z Sensitized Radiotherapy with CD73 Blockade to Boost Tumor Immunotherapy.

Radiation therapy (RT) has the capacity to induce immunogenic death in tumor cells, thereby potentially inducing in situ vaccination (ISV) to prime systemic antitumor immune responses. However, RT alone is often faced with various limitations during ISV induction, such as insufficient X-ray deposition and an immunosuppressive microenvironment. To overcome these limitations, we constructed nanoscale coordination particles AmGd-NPs by self-assembling high-Z metal gadolinium (Gd) and small molecular CD73 inhibitor AmPCP. Then, AmGd-NPs could synergize with RT to enhance immunogenic cell death, improve phagocytosis, and promote antigen presentation. Additionally, AmGd-NPs could also gradually release AmPCP to inhibit CD73's enzymatic activity and prevent the conversion of extracellular ATP to adenosine (Ado), thereby driving a proinflammatory tumor microenvironment that promotes DC maturation. As a result, AmGd-NPs sensitized RT induced potent in situ vaccination and boosted CD8+ T cell-dependent antitumor immune responses against both primary and metastatic tumors, which could also be potentiated by immune checkpoint inhibitory therapy.

In Situ Vaccination with Mitochondria-Targeting Immunogenic Death Inducer Elicits CD8+ T Cell-Dependent Antitumor Immunity to Boost Tumor Immunotherapy.

In situ vaccination can elicit systemic antitumor immunity to potentiate immune checkpoint blockade (ICB) in poorly immunogenic tumors. Herein, an immunogenic cell death (ICD) inducer for in situ vaccination, which is based on a mitochondria-targeting modification of fenofibric acid (FFa), a lipid-lowering drug with potential inhibitory efficacy of respiratory complex I is developed. Mitochondria-targeting FFa (Mito-FFa) inhibits complex I efficiently and increases mitochondrial ROS (mtROS) generation, which further triggers endoplasmic reticulum (ER) stress with unprecedented calreticulin (CRT) exposure on tumor cellular membranes. Moreover, the generated mtROS also oxidizes mitochondrial DNA (mtDNA) and promotes it leakage into the cytoplasm for cGAS-STING-dependent type I interferon (IFN-I) secretion. The synchronous CRT exposure and IFN-I secretion successively improve the uptake of tumor antigens, maturation of dendritic cells (DCs) and cross-priming of CD8+ T cells. In a poorly immunogenic 4T1 tumor model, a single intratumoral (i.t.) Mito-FFa injection turns immune-cold tumors into hot ones and elicits systemic tumor-specific CD8+ T cells responses against primary and metastatic tumors. Furthermore, the synergistic effect with PD-L1 blockade and good bio-safety of i.t. Mito-FFa administration suggest the great translational potential of Mito-FFa in tumor immunotherapy.

Scintillator-based radiocatalytic superoxide radical production for long-term tumor DNA damage.

Photocatalytic materials absorb photons ranging from the ultraviolet to near-infrared region to initiate photocatalytic reactions and have broad application prospects in various fields. However, high-energy ionizing radiations are rarely involved in photocatalytic research. In this study, we proposed a high-energy radiation-based photocatalysis method, namely "radiocatalysis", and prepared a TiO2-coated lanthanide pyrosilicate scintillator (LnPS@TiO2) as the radiocatalytic material. The lanthanide pyrosilicate post-radiation scintillators can efficiently convert radiation energy into ultraviolet energy, which can be resonantly transferred to TiO2 to selectively generate high-yield superoxide radicals (). Compared with traditional radiotherapy, this radiocatalytic process can significantly kill cancer cells while achieving long-term DNA damage by inhibiting the DNA self-repair process. Our research expands the energy response range of photocatalysis and is expected to extend radiocatalysis to the tumor treatment field.

High-Z-Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination.

In situ tumor vaccination is preliminarily pursued to strengthen antitumor immune response. Immunogenic tumor cell death spontaneously releases abundant antigens and adjuvants for activation of dendritic cells, providing a paragon opportunity for establishing efficient in situ vaccination. Herein, Phy@PLGdH nanosheets are constructed by integrating physcion (Phy, an inhibitor of the pentose phosphate pathway (PPP)) with layered gadolinium hydroxide (PLGdH) nanosheets to boost radiation-therapy (RT)-induced immunogenic cell death (ICD) for potent in situ tumor vaccination. It is first observed that sheet-like PLGdH can present superior X-ray deposition and tumor penetrability, exhibiting improved radiosensitization in vitro and in vivo. Moreover, the destruction of cellular nicotinamide adenine dinucleotide phosphate (NADPH) and nucleotide homeostasis by Phy-mediated PPP intervention can further amplify PLGdH-sensitized RT-mediated oxidative stress and DNA damage, which correspondingly results in effective ICD and enhance the immunogenicity of irradiated tumor cells. Consequently, Phy@PLGdH-sensitized RT successfully primes robust CD8+ -T-cell-dependent antitumor immunity to potentiate checkpoint blockade immunotherapies against primary and metastatic tumors.

Systemic immune responses to irradiated tumours via the transport of antigens to the tumour periphery by injected flagellate bacteria.

Because the tumour microenvironment is typically immunosuppressive, the release of tumour antigens mediated by radiotherapy or chemotherapy does not sufficiently activate immune responses. Here we show that, following radiotherapy, the intratumoural injection of a genetically attenuated strain of Salmonella coated with antigen-adsorbing cationic polymer nanoparticles caused the accumulation of tumour antigens at the tumour's periphery. This enhanced the crosstalk between the antigens and dendritic cells, and resulted in large increases in activated ovalbumin-specific dendritic cells in vitro and in systemic antitumour effects, and extended survival in multiple tumour models in mice, including a model of metastasis and recurrence. The antitumour effects were abrogated by the antibody-mediated depletion of CD8+ T cells, indicating that systemic tumour regression was caused by adaptive immune responses. Leveraging flagellate bacteria to transport tumour antigens to the periphery of tumours to potentiate the activation of dendritic cells may open up new strategies for in situ cancer vaccination.

Zoledronic Acid-Gadolinium Coordination Polymer Nanorods for Improved Tumor Radioimmunotherapy by Synergetically Inducing Immunogenic Cell Death and Reprogramming the Immunosuppressive Microenvironment.

Radiation therapy can potentially elicit a systemic immune response and cause the regression of nonirradiated tumors, and the checkpoint blockade immunotherapies have been introduced to improve their clinical response rate. However, the therapeutic benefits of radioimmunotherapy are still far from satisfactory. Herein, the self-assembled "carrier-free" coordination polymer nanorods are constructed based on gadolinium and zoledronic acid, which can deposit X-ray for improved reactive oxygen species production to induce potent immunogenic cell death (ICD), simultaneously deplete tumor-associated macrophages with regulatory cytokines inhibition, respectively. With the potent ICD induction and reprogrammed immunosuppressive microenvironment, this synergetic strategy can promote antigen presentation, immune priming and T-cell infiltration, and potentiate checkpoint blockade immunotherapies against primary, distant, and metastatic tumors.

Photosynthetic Microorganisms-Based Biophotothermal Therapy with Enhanced Immune Response.

The production of oxygen by photosynthetic microorganisms (PSMs) has recently attracted interest concerning the in vivo treatment of multiple diseases for their photosynthetic oxygen production in vivo, since PSMs have good biological safety. Here, the first evidence that PSMs can be used as a photothermal source to perform biophotothermal therapy (bio-PTT) is provided. In vitro and in vivo experiments proved that PSMs can generate heat for the direct elimination of tumors and release a series of pathogen-associated molecular patterns and adjuvants for immune stimulation under light irradiation. Bio-PTT enabled a local tumor inhibition rate exceeding 90% and an abscopal tumor inhibition rate exceeding 75%. This strategy also produced a stronger antitumor immune memory effect to prevent tumor recurrence. The bio-PTT strategy provides a novel direction for photothermal therapy as it simultaneously produces local and abscopal antitumor effects.

Copper-Based Nanoscale Coordination Polymers Augmented Tumor Radioimmunotherapy for Immunogenic Cell Death Induction and T-Cell Infiltration.

Insufficient T-cell infiltration seriously hinders the efficacy of tumor immunotherapy. Induction of immunogenic cell death (ICD) is a potentially feasible approach to increase T-cell infiltration. Since ionizing radiation can only induce low-level ICD, this study constructs Cu-based nanoscale coordination polymers (Cu-NCPs) with mixed-valence (Cu+ /Cu2+ ), which can simultaneously and independently induce the generation of Cu+ -triggered hydroxyl radicals and Cu2+ -triggered GSH elimination, to synergize with radiation therapy for potent ICD induction. Markedly, this synergetic therapy remarkably enhances dendritic cell maturation and promotes antitumor CD8+ T-cell infiltration, thereby potentiating the development of checkpoint blockade immunotherapies against primary and metastatic tumors.

Nanoscale coordination polymers induce immunogenic cell death by amplifying radiation therapy mediated oxidative stress.

Radiation therapy can potentially induce immunogenic cell death, thereby priming anti-tumor adaptive immune responses. However, radiation-induced systemic immune responses are very rare and insufficient to meet clinical needs. Here, we demonstrate a synergetic strategy for boosting radiation-induced immunogenic cell death by constructing gadolinium-hemin based nanoscale coordination polymers to simultaneously perform X-ray deposition and glutathione depletion. Subsequently, immunogenic cell death is induced by sensitized radiation to potentiate checkpoint blockade immunotherapies against primary and metastatic tumors. In conclusion, nanoscale coordination polymers-sensitized radiation therapy exhibits biocompatibility and therapeutic efficacy in preclinical cancer models, and has the potential for further application in cancer radio-immunotherapy.

Light-controlled oxygen production and collection for sustainable photodynamic therapy in tumor hypoxia.

Hypoxia exists in most malignant tumors and often contributes to therapy resistance, especially for aerobic treatments such as photodynamic therapy (PDT) and radiotherapy. Here, we developed a novel light-controlled sustainable PDT in which light was used to help photosynthetic microorganisms (Chlorella) produce oxygen, and perfluorocarbon was used to enrich oxygen around the photosensitizer for sustained oxygen supply. After light stops, Chlorella further acts as an adjuvant to promote dendritic cell (DC) activation, promoting the antitumor immune response. We showed that sustainable PDT could continuously provide oxygen for photosensitizers and avoid PDT-induced local hypoxia. More importantly, sustainable PDT also promoted the activation of DCs and amplified the antitumor immune effects. Therefore, this novel strategy provides an effective but simple method for improving PDT in both tumor hypoxia and normoxia, and enhancing the antitumor immunity may be a new anti-resistance strategy for treating patients with advanced-stage cancer.

Novel copper-based and pH-sensitive nanomedicine for enhanced chemodynamic therapy.

We utilized albumin as a reducing agent to establish novel copper-based and pH-sensitive nanocarrier CuNPs with abundant Cu+, which can encapsulate histone deacetylase (HDAC) inhibitor vorinostat to form uniform and stable nanomedicine V-CuNPs for synergistic chromatin remodelling and chemodynamic therapy.

Synergy of Tumor Microenvironment Remodeling and Autophagy Inhibition to Sensitize Radiation for Bladder Cancer Treatment.

Tumor hypoxia, acidosis, and excessive reactive oxygen species (ROS) were the main characteristics of the bladder tumor microenvironment (TME), and abnormal TME led to autophagy activation, which facilitated cancer cell proliferation. The therapeutic efficacy of autophagy inhibitors might also be impeded by abnormal TME. To address these issues, we proposed a new strategy that utilized manganese dioxide (MnO2) nanoparticles to optimize the abnormal TME and revitalize autophagy inhibitors, and both oxygenation and autophagy inhibition may sensitize the tumor cells to radiation therapy. Methods: By taking advantage of the strong affinity between negatively charged MnO2 and positively charged chloroquine (CQ), the nanoparticles were fabricated by integrating MnO2 and CQ in human serum albumin (HSA)-based nanoplatform (HSA-MnO2-CQ NPs). Results: HSA-MnO2-CQ NPs NPs efficiently generated O2 and increased pH in vitro after reaction with H+/H2O2 and then released the encapsulated CQ in a H+/H2O2 concentration-dependent manner. The NPs restored the autophagy-inhibiting activity of chloroquine in acidic conditions by increasing its intracellular uptake, and markedly blocked hypoxia-induced autophagic flux. In vivo studies showed the NPs improved pharmacokinetic behavior of chloroquine and effectively accumulated in tumor tissues. The NPs exhibited significantly decreased tumor hypoxia areas and increased tumor pH, and had remarkable autophagy inhibition efficacy on bladder tumors. Finally, a significant anti-tumor effect achieved by the enhanced autophagy inhibition and radiation sensitization. Conclusions: HSA-MnO2-CQ NPs synergistically regulated the abnormal TME and inhibited autophagic flux, and effectively sensitized radiation therapy to treat bladder cancers.

Synergy of hypoxia relief and chromatin remodeling to overcome tumor radiation resistance.

Radiotherapy (RT) is one of the most extensive and effective approaches available for clinical tumor treatment. However, tumor microenvironments including hypoxia and histone deacetylase (HDAC) overexpression could induce radiation resistance, leading to tumor recurrence. Herein, nanoparticles (CAT-SAHA@PLGA) encapsulating catalase and HDAC inhibitor SAHA exhibited protected catalytic activity of catalase and prolonged the pharmacokinetic exposure of the HDAC inhibitor. Overall, the established CAT-SAHA@PLGA nanoparticles could overcome radiation resistance by synergistically increasing tumor oxygenation and inhibiting HDAC activity.

Erratum: Two-stage oxygen delivery for enhanced radiotherapy by perfluorocarbon nanoparticles: Erratum.

[This corrects the article DOI: 10.7150/thno.27598.].

Bifunctional liposomes reduce the chemotherapy resistance of doxorubicin induced by reactive oxygen species.

Doxorubicin (DOX) liposome is a widely used nano-medicine for colorectal cancer treatment. However, doxorubicin therapy increases the level of reactive oxygen species (ROS) in tumor cells, such as hydrogen peroxide (H2O2), which can stabilize hypoxia-inducible-factor-1α (HIF-1α). In a tumor hypoxic microenvironment, HIF-1 can up-regulate tumor-resistance related proteins, including P-glycoprotein (P-gp), glucose transporter 1 (GLUT-1), and matrix metalloproteinase 9 (MMP-9), leading to tumor tolerance to chemotherapy. The functional inhibition of HIF-1 can overcome this resistance and enhance the efficacy of tumor therapy. Here, we encapsulated one of the most effective HIF-1 inhibitors, acriflavine (ACF), and DOX in liposomes (DOX-ACF@Lipo) to construct bifunctional liposomes. ACF and DOX, released from DOX-ACF@Lipo, could effectively suppress the function of HIF-1 and the process of DNA replication, respectively. Consequently, the bifunctional liposome has great potential to be applied in clinics to overcome chemotherapy resistance induced by hypoxia.

Perfluorocarbon nanoparticle-mediated platelet inhibition promotes intratumoral infiltration of T cells and boosts immunotherapy.

Cancer immunotherapy can stimulate and enhance the ability of the immune system to recognize, arrest, and eliminate tumor cells. Immune checkpoint therapies (e.g., PD-1/PD-L1) have shown an unprecedented and durable clinical response rate in patients among various cancer types. However, a large fraction of patients still does not respond to these checkpoint inhibitors. The main cause of this phenomenon is the limited T-cell infiltration in tumors. Therefore, additional strategies to enhance T-cell trafficking into tumors are urgently needed to improve patients' immune responses. In this study, we screened an array of perfluorocarbon compounds, reporting that albumin-based perfluorotributylamine nanoparticles (PFTBA@Alb) can effectively increase the permeability of tumor blood vessels, and no distinct side effects were found on normal blood vessels. After i.v. administration of PFTBA@Alb, the number of tumor-infiltrating CD8+ and CD4+ T cells showed an obvious rising trend. More important, a striking tumor inhibition rate, reaching nearly 90%, was observed when combining PFTBA@Alb with anti-PD-L1 antibody. These findings suggest that PFTBA@Alb can be regarded as an enhancer for anti-PD-L1 immunotherapy.