ACS Applied Materials & Interfaces
·
2020
·
IF 8.758
Qi Shang,Shiyao Zhou,Yue Jiang,Dong Wang,Jiqian Wang,Aixin Song,Yuxia Luan
Immune checkpoint blockade of the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway via an antibody is a potent strategy for T cell remodeling. Nevertheless, the potency of the antibody is partly compromised by its high price, instability, risk of autoimmune disease, and so forth. Small-molecule inhibitors are interesting alternatives to antibodies. However, tumor-specific delivery of small-molecule inhibitors to the target site for boosting the interruption of the PD-L1/PD-1 pathway is rarely reported. Herein, we designed a tumor-specific delivery nanoplatform that could efficiently deliver the small-molecule inhibitor to the precise target site, greatly enhancing the blocking effect of the PD-L1/PD-1 pathway. Hyaluronic acid (HA) was conjugated with chlorin e6 (Ce6), resulting in a HA–Ce6 conjugate (HC). The nanoplatform was constructed by the HC micelles with the encapsulation of small-molecule inhibitor, BMS 202 (BMS), to form BMS/HC micelles. The target property of HA, combined with the hyaluronidase-induced degradation of HA in the tumor site, enables the as-prepared micelles with tumor-specific delivery of BMS for blocking the PD-L1/PD-1 pathway. With cooperative treatment with the photosensitizer Ce6, the present therapeutic nanoplatform demonstrated excellent photoimmunotherapy for tumor regression in distant tumors and lung metastasis. This strategy of tumor-specific delivery of small-molecule inhibitors provides an effective pathway to strengthen the blocking efficacy of PD-L1/PD-1 on effective photoimmunotherapy.
研究领域:
癌症研究
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免疫疗法
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纳米医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Chengxun Li,Fei Chen,Jianing Wu,Jun Ren,Yingzhu Li,Shengjie Li,Zuguang Xia
Antibody drug conjugates (ADCs) offer targeted cancer therapy but face limitations in drug loading, stability, and immune modulation. Here, antibody DNA nanostructure conjugates (ADNCs) is reported as a next-generation platform that overcomes these challenges. By leveraging the programmable architecture of DNA nanostructures, ADNCs achieve high, tunable drug payloads without inducing antibody aggregation—a major drawback of conventional ADCs. In CT26 cells, gemcitabine-loaded ADNCs trigger dual cell death pathways—caspase-3-mediated apoptosis and RIP3-mediated necroptosis—enhancing tumor cell killing. In the CT26 syngeneic model, ADNCs suppress tumor growth with no observable toxicity and, notably, activate anti-tumor immunity without upregulating PD-1, suggesting avoidance of T-cell exhaustion. Critically, ADNCs maintain efficacy in patient-derived xenograft (PDX) models despite tumor heterogeneity. The study presents a novel, stable, and scalable antibody-drug conjugate (ADC)-inspired platform that integrates high payload delivery capacity with enhanced and adjustable drug-loading capabilities—characteristics that are seldom achieved in existing ADC technologies—thereby demonstrating translational potential for applications in precision oncology.
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PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Yu Ji,Suchen Qu,Gaoyu Shi,Liansheng Fan,Jing Qian,Zhaorui Sun,Feng Lu,Xin Han
Hypoxia is one of the most typical features among various types of solid tumors, which creates an immunosuppressive tumor microenvironment (TME) and limits the efficacy of cancer treatment. Alleviating hypoxia becomes a key strategy to reshape hypoxic TME which improves cancer immunotherapy. However, it remains challenging to perform tumor precision therapy with controllable switches through hypoxia-activated gene editing and prodrugs to alleviate hypoxia. In this study, silica-coated second near-infrared window (NIR-II) emitting silver sulfide quantum dots are used as the carrier to load the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9) system to target hypoxia-inducible factor-1 (HIF-1α) and guide tumor-targeted imaging. To reduce the off-target effects in nontumor cells and better control safety risks, a TME-triggered cascade-activation nanodiagnostic and therapeutic platform (AA@Cas-H@HTS) is designed, which achieves the hypoxia activation of prodrug tirapazamine (TPZ) and spatiotemporal release of CRISPR/Cas9 ribonucleoprotein. Tumor hypoxia is greatly alleviated by the synergistic function of HIF-1α depletion by gene editing and TPZ activation. Importantly, targeting HIF-1α disrupts the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway, which effectively reshapes the immune-suppressive TME and activates T cell-mediated antitumor immunity. Taken together, we have provided a TME-triggered cascade-activation nanoplatform to alleviate hypoxia for improved cancer immunotherapy.
研究领域:
癌症生物学
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免疫学
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纳米技术
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分子生物学
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诊疗学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
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IF 8
Fengli Huang,Qun Zhang,Jie Xiao,Xin Zhang,Xingzhi Han,Xiao Shi,Jing Hu,Li Li,Xiaoping Qian
Purpose Recent studies have shown that traditional Chinese medicine (TCM), such as gambogic acid (GA), is involved in the regulation of tumor immune microenvironment and can be combined with other anti-tumor treatment strategies. Here, we used GA as an adjuvant to construct a nano-vaccine to improve the anti-tumor immune response of colorectal cancer (CRC).Materials and Methods We used a previously reported two-step emulsification method to obtain poly (lactic-co-glycolic acid) /GA nanoparticles (PLGA/GA NPs), and then CT26 colon cancer cell membrane (CCM) was used to obtain CCM-PLGA/GA NPs. This novel nano-vaccine, CCM-PLGA/GA NPs, was co-synthesized with GA as an adjuvant and neoantigen provided by CT26 CCM. We further confirmed the stability, tumor targeting, and cytotoxicity of CCM-PLGA/GA NPs. The regulatory effect on the tumor immune microenvironment, the anti-tumor efficacy, and the combined anti-tumor efficacy with anti-PD-1 monoclonal Antibodies (mAbs) of this novel nano-vaccine was also detected in vivo.Results We successfully constructed the CCM-PLGA/GA NPs. In vitro and in vivo tests showed low biological toxicity, as well as the high tumor-targeting ability of the CCM-PLGA/GA NPs. Besides, we revealed a remarkable effect of CCM-PLGA/GA NPs to activate the maturation of dendritic cells (DCs) and the formation of a positive anti-tumor immune microenvironment.Conclusion This novel nano-vaccine constructed with GA as the adjuvant and CCM providing the tumor antigen can not only directly kill tumors by enhancing the ability of GA to target tumors, but also indirectly kill tumors by regulating tumor immune microenvironment, providing a new strategy for immunotherapy of CRC.
研究领域:
药学
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免疫学
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肿瘤学
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纳米技术
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中医药
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Zhiyuan Cheng,Yijie Wang,Yao Zhang,Chan Zhang,Mengru Wang,Wei Wang,Jiacheng He,Yang Wang,Hankun Zhang,Qiansen Zhang,Chunyong Ding,Deyan Wu,Linlin Yang,Mingyao Liu,Weiqiang Lu
Nowadays, small-molecule drugs have become an indispensable part of tumor immunotherapy. Accumulating evidence has indicated that specifically blocking PGE2/EP4 signaling to induce robust antitumor immune response represents an attractive immunotherapy strategy. Herein, a 2H-indazole-3-carboxamide containing compound 1 was identified as a EP4 antagonist hit by screening our in-house small-molecule library. Systematic structure–activity relationship exploration leads to the discovery of compound 14, which displayed single-nanomolar EP4 antagonistic activity in a panel of cell functional assays, high subtype selectivity, and favorable drug-like profiles. Moreover, compound 14 profoundly inhibited the up-regulation of multiple immunosuppression-related genes in macrophages. Oral administration of compound 14, either as monotherapy or in combination with an anti-PD-1 antibody, significantly impaired tumor growth via enhancing cytotoxic CD8+ T cell-mediated antitumor immunity in a syngeneic colon cancer model. Thus, these results demonstrate the potential of compound 14 as a candidate for developing novel EP4 antagonists for tumor immunotherapy.
研究领域:
肿瘤学
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免疫学
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药理学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Yaqing Kang,Jiao Yan,Xiaoqing Han,Xingbo Wang,Yanjing Wang,Panpan Song,Xiaochen Su,Abdur Rauf,Xuefei Jin,Fang Pu,Haiyuan Zhang
Cancer immunotherapy is developing as the mainstream strategy for treatment of cancer. However, the interaction between the programmed cell death protein-1 (PD-1) and the programmed death ligand 1 (PD-L1) restricts T cell proliferation, resulting in the immune escape of tumor cells. Recently, immune checkpoint inhibitor therapy has achieved clinical success in tumor treatment through blocking the PD-1/PD-L1 checkpoint pathway. However, the presence of M2 tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) will inhibit antitumor immune responses and facilitate tumor growth, which can weaken the effectiveness of immune checkpoint inhibitor therapy. The repolarization of M2 TAMs into M1 TAMs can induce the immune response to secrete proinflammatory factors and active T cells to attack tumor cells. Herein, hollow iron oxide (Fe3O4) nanoparticles (NPs) were prepared for reprogramming M2 TAMs into M1 TAMs. BMS-202, a small-molecule PD-1/PD-L1 inhibitor that has a lower price, higher stability, lower immunogenicity, and higher tumor penetration ability compared with antibodies, was loaded together with pH-sensitive NaHCO3 inside hollow Fe3O4 NPs, followed by wrapping with macrophage membranes. The formed biomimetic FBN@M could produce gaseous carbon dioxide (CO2) from NaHCO3 in response to the acidic TME, breaking up the macrophage membranes to release BMS-202. A series of in vitro and in vivo assessments revealed that FBN@M could reprogram M2 TAMs into M1 TAMs and block the PD-1/PD-L1 pathway, which eventually induced T cell activation and the secretion of TNF-α and IFN-γ to kill the tumor cells. FBN@M has shown a significant immunotherapeutic efficacy for tumor treatment.
研究领域:
生物医学工程
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肿瘤免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Jingshu Meng,Xiao Yang,Jing Huang,Zhan Tuo,Yan Hu,Zhiyun Liao,Yu Tian,Suke Deng,Yue Deng,Zhiyuan Zhou,Jonathan F. Lovell,Honglin Jin,Yang Liu,Kunyu Yang
Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. Due to the insensitivity of advanced HCC cells to traditional chemotherapies, low drug accumulation, and limited drug residence time in the peritoneal cavity, the therapeutic effects of malignant ascites in HCC are not satisfactory. In this study, an injectable hydrogel drug delivery system based on chitosan hydrochloride and oxidized dextran (CH-OD) is designed to load sulfasalazine (SSZ), an FDA-approved drug with ferroptosis-inducing ability, for effective tumor-killing and activation of anti-tumor immunity. Compared to free SSZ, SSZ-loaded CH-OD (CH-OD-SSZ) hydrogel exhibits greater cytotoxicity and induces higher levels of immunogenic ferroptosis. In the preclinical model of hepatoma ascites, intraperitoneal administration of CH-OD-SSZ hydrogel can significantly suppress tumor progression and improve the immune landscape. Both in vitro and in vivo, CH-OD-SSZ hydrogel induces the repolarization of macrophages to an M1-like phenotype and promotes the maturation and activation of dendritic cells. Combination treatment with CH-OD-SSZ hydrogel and anti-programmed cell death protein 1 (PD-1) immunotherapy achieves more than 50% ascites regression and generates long-term immune memory. Collectively, CH-OD-SSZ hydrogel exhibits promising therapeutic potential in the treatment of peritoneal dissemination and malignant ascites in advanced HCC, especially when combined with anti-PD-1 immunotherapy.
研究领域:
肿瘤学
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药学
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生物医学工程
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免疫学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Yaxin Wang,Fang Luo,Pengcheng Zhang,Hong Niu,Yaomin Tan,Yizhi Zhang,Ziyan Tang,Lina Du,Yiguang Jin,Xu Jin
Neuroinflammation is a key pathogenic process in multiple central nervous system (CNS) disorders. It can lead to neuronal injury and cognitive decline through excessive glial activation and aberrant engagement of the programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint axis. To address these pathologies, we engineered a PD-1-enriched macrophage-membrane, lactoferrin-modified, PEGylated, glycyrrhizic-acid–loaded biomimetic hybrid liposome (PMLpGL) for dual, precise modulation of the neuroinflammatory microenvironment. PMLpGL alleviates neuronal inhibitory signaling by reversibly sequestering excess PD-L1 via membrane-anchored PD-1, while its cargo GA suppresses high-mobility group box-1 (HMGB1)-driven inflammatory cascades, thereby returning inducible PD-1/PD-L1 expression and glial activation toward homeostasis. Physicochemical characterization showed a hydrodynamic diameter of 165 ± 3 nm and a zeta potential of −10.2 ± 0.2 mV. Engineered macrophage membranes displayed marked PD-1 overexpression, and ligand-depletion saturation assays demonstrated specific, saturable PD-1/PD-L1 binding. In a Transwell blood–brain barrier (BBB) model, PMLpGL achieved a 24-h permeability of 22.86 ± 0.14 %, indicating robust in-vitro BBB traversal. In vivo fluorescence imaging showed peak brain accumulation at 24 h with retention to 48 h; liquid chromatography–tandem mass spectrometry further confirmed brain targeting and persistence—at 12 h, brain GA with PMLpGL was ∼48-fold higher than free drug and remained quantifiable at 48 h. Pharmacodynamic evaluations in cells and mice demonstrated that PMLpGL suppresses glial activation and normalizes inducible checkpoint expression; reshapes the cytokine milieu by lowering IL-6, IL-1β, TNF-α, and HMGB1 while increasing IL-10, TGF-β, and brain-derived neurotrophic factor; and restores the synaptic protein synapsin-1. Correspondingly, PMLpGL significantly improved cognition in open-field, novel object recognition, and Morris water maze tests. Collectively, PMLpGL combines PD-1 decoy sequestration with GA-mediated upstream immunomodulation to attenuate neuroinflammatory cascades, protect neurons, and reverse cognitive deficits. By pairing BBB compatibility with microenvironment-precise regulation, this platform offers a promising therapeutic strategy for CNS diseases associated with cognitive decline.
研究领域:
神经科学
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免疫学
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纳米医学
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药学
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中枢神经系统疾病
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2019
·Vol. 29
·期 12
·1806916
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IF 15.621
Xiaowei Liu,Yanlin Feng,Guangchao Xu,Yang Chen,Ya Luo,Jinen Song,Yu Bao,Jiqiao Yang,Chune Yu,Yanna Li,Haoyu Ye,Bowen Ke,Bo Chen,Jianping Hu,Jie Xu,Huan Meng,Haiyuan Zhang,Hubing Shi
The combination of BRAF/MEK-targeted therapy with immune checkpoint blockade is regarded as a promising regimen for patients with metastatic melanoma due to their complementary advantages. However, MEK-inhibitor-induced T-cell toxicity impedes effective cooperation. In this experiment, a pH-responsive on-demand controlled release mesoporous silica nanoparticles (MSNPs) system is designed. Fluorescein-isothiocyanate-loaded MSNP can be specifically delivered into tumor cells rather than T-cells. MEK-inhibitor-loaded MSNP avoids proliferative and functional inhibitions of T-cells, while preserving growth suppression of tumor cells in vitro. In an in vivo model, MSNP encapsulation reverses the MEK-inhibitor-induced suppression of activated CD8 + T-cells, and enhances the secretion of INF-γ and IL-2. The combination of BRAF inhibitor plus MSNP-loaded MEK inhibitor and anti-PD-1 antibody synergistically inhibits tumor growth via promoting robust immune-related antitumor response. This work provides a novel and generalized framework for combining T-cell-impaired targeted therapy and immune checkpoint blockade by using a nanoparticle-based delivery system.
研究领域:
肿瘤学
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药理学
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纳米技术
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免疫疗法
✓ 已验证
DOI
高影响因子
ACS Sensors
·
2025
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IF 9.1
Zhenguo Zhang,Xue Li,Shuo Zhang,Mingshuang Zheng,Fangping Yuan,Shushen Li,Bei Yuan,Lisheng Liu,Xin Du
Although immunotherapy has become an established approach in cancer treatment, not all patients exhibit a positive response. Current research on PD-1 primarily focuses on immune cells using conventional methods, yet PD-1 expression on tumor cells is also widespread and plays an increasingly critical role in assessing immunotherapy efficacy. To address this, we developed an electrochemical biosensor capable of specifically detecting PD-1 at both the protein and tumor cellular levels in situ, eliminating the need for sample fixation and thereby streamlining the analytical process. Additionally, our probe enables simultaneous localization analysis of PD-1 through fluorescence signaling. The biosensor integrates a bifunctional probe composed of a nanometal–organic framework (MOF, ZIF-8) conjugated with quantum dots (QDs) and an electrode modified with a carbon nanotube (CNT)–gold nanoparticle (AuNP) nanocomposite. The morphology and performance of the nanocomposite were thoroughly characterized, and the resulting PD-1 biosensor demonstrates high specificity, reproducibility, and sensitivity. To facilitate clinical translation, we successfully applied the biosensor to detect differential PD-1 expression across various tumor cell lines and cancer tissues. This study establishes that our dual-mode electrochemical and fluorescent sensing platform provides a powerful tool for in situ PD-1 detection on tumor cells, offering valuable insights for evaluating tumor immunotherapy responses.
研究领域:
癌症免疫治疗
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生物传感器
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纳米材料
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电化学
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分子诊断
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产品关联
DOI
PubMed
高影响因子
Frontiers in Bioscience-Landmark
·
2023
·Vol. 28
·期 12
·327
·
IF 3.1
Ruoxia Wu,Jiaqing Xiong,Ting Zhou,Zhen Zhang,Zhen Huang,Sha Tian,Yongli Wang
Objective: The use of immune checkpoint inhibitors (ICIs) provides promising strategies for hepatocellular carcinoma (HCC) treatment. This study aimed to explore impact and underlying mechanism of the combination therapy of quercetin and anti-programmed cell death 1 (anti-PD-1) antibody on HCC. Methods: Orthotopically transplanted HCC tumors in mice were treated with quercetin, anti-PD-1 antibody, or a combination of both therapies. Histopathological changes and programmed cell death ligand 1 (PD-L1) expression were characterized by hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining. The diversity and differences of gut microbiota (GM) were evaluated through 16S rRNA sequencing. Levels of macrophage immunity-related cytokines were quantified by enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (RT-qPCR), and Western blot. Results: Combination therapy reduced necrosis, fibrosis, and PD-L1 expression in liver tissues. Additionally, combination therapy reduced GM imbalance and increased abundance of Firmicutes, Actinobacteria, and Verrucomicrobiota at the phylum level as well as Dubosiella and Akkermansia at the genus level. Combination therapy improved macrophage immunity, raised the expressions of CD8a, CD4, CD11b, interleukin (IL)-10, and interferon (IFN)-γ , and declined the expressions of IL-4, IL-6, toll-like receptor 4 (TLR4), an inhibitor of nuclear factor κBα (IκBα), and the NFκB subunit p65. Upon combination therapy, expressions of M2 macrophage-related genes arginase-1 (Arg-1), IL-10, transforming growth factor-β (TGF-β), and matrix metalloproteinase-9 (MMP-9) were upregulated. Instead, M1 macrophage-related genes IL-6, IL-12a, IL-1β, and tumor necrosis factor-α (TNF-α) were downregulated. Conclusions: Quercetin/anti-PD-1 antibody combination therapy reshaped HCC tumor microenvironment in mice in parallel with regulating the GM and macrophage immunity.
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DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2024
·Vol. 30
·期 7
·e14791
·
IF 4.8
Guangcai Shao,Xiangguo Cui,Yiliang Wang,Shuyan Luo,Chuanyu Li,Yu Jiang,Dasheng Cai,Nu Li,Xiang Li
Introduction Glioblastoma (GBM) remains a challenging brain tumor to treat, with limited response to PD-1 immunotherapy due to tumor-associated macrophages (TAMs), specifically the M2 phenotype. This study explores the potential of MS4A4A (membrane spanning four domains, subfamily A, member 4A) inhibition in driving M2 macrophage polarization toward the M1 phenotype via the ferroptosis pathway to enhance the effectiveness of immunotherapy in GBM. Methods Single-cell RNA sequencing and spatial transcriptomic analyses were employed to characterize M2 macrophages and MS4A4A expression in GBM. In vitro studies utilizing TAM cultures, flow cytometry, and western blot validations were conducted to assess the impact of MS4A4A on the tumor immune microenvironment and M2 macrophage polarization. In vivo models, including subcutaneous and orthotopic transplantation in mice, were utilized to evaluate the effects of MS4A4A knockout and combined immune checkpoint blockade (ICB) therapy on tumor growth and response to PD-1 immunotherapy. Results Distinct subsets of GBM-associated macrophages were identified, with spatial distribution in tumor tissue elucidated. In vivo experiments demonstrated that inhibiting MS4A4A and combining ICB therapy effectively inhibited tumor growth, reshaped the tumor immune microenvironment by reducing M2 TAM infiltration and enhancing CD8 + T-cell infiltration, ultimately leading to complete tumor eradication. Conclusion MS4A4A inhibition shows promise in converting M2 macrophages to M1 phenotype via ferroptosis, decreasing M2-TAM infiltration, and enhancing GBM response to PD-1 immunotherapy. These findings offer a novel approach to developing more effective immunotherapeutic strategies for GBM.
研究领域:
肿瘤学
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免疫学
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神经科学
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分子生物学
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癌症治疗
✓ 已验证
DOI
PubMed
高影响因子
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