JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-18
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IF 10.6
Zou Ting,Huang Yun,Zhou Zongtao,He Shuangyan,Liu Jia,Chen Yalan,Liu Hongdu,Luo Zhonghui,Liu Miaoxin,Wei Hua,Yu CuiYun
Clinical treatment of hepatocellular carcinoma (HCC) with 5-fluorouracil (5-FU), the primary anticancer agent, remains unsatisfactory due to the glutathione (GSH)-associated drug resistance and immunosuppressive microenvironment of HCC. To develop a facile yet robust strategy to overcome 5-FU resistance for enhanced immunotherapy treatment of HCC via all dimensional GSH exhaustion, we report in this study construction of a minimalist prodrug consisting of 5-FU linked to an indoleamine-(2,3)-dioxygenase (IDO) inhibitor (IND) via a disulfide bridge, FU-SS-IND that can further self-assemble into stabilized nanoparticles, FU-SS-IND NPs. Specifically, besides the disulfide linker-induced GSH exhaustion, IND inhibits GSH biosynthesis and enhances the effector function of T cells for turning a “cold” tumor to a “hot” one, which synergistically achieving a tumor inhibition rate (TIR) of 92.5% in a 5-FU resistant mice model. Most importantly, FU-SS-IND NPs could upregulate programmed death ligand 1 (PD-L1) expression on the surface of tumor cells, which enables facile combination with immune checkpoint blockade (ICB) for a ultimate prolonged survival lifetime of 5-FU-resistant tumors-bearing mice. Overall, the minimalist bioreducible nano-prodrug developed herein demonstrates great translatable potential for efficiently reversing drug resistance and enhancing immunotherapy of HCC.
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高影响因子
DALTON TRANSACTIONS
·
2022
·Vol. 51
·期 33
·12604-12619
·
IF 4.569
Zuojie Li,Linming Li,Wenhuan Zhao,Bin Sun,Zhifang Liu,Min Liu,Jun Han,Zhengping Wang,Dacheng Li,Qingpeng Wang
To develop new anti-metastasis chemotherapeutic drugs, a series of flurbiprofen (FLP) and zaltoprofen (ZTP) platinum(IV) complexes targeting COX-2, PD-L1 and DNA was prepared and investigated. Complex 2 with dual FLP ligands displays promising antitumor activities in vitro and exhibits much potential in overcoming drug resistance. More importantly, the antitumor evaluation in vivo demonstrates that complex 2 possesses promising inhibition of cancer growth and metastasis simultaneously. Further investigation of the mechanism revealed the multi-specific antitumor function of complex 2. It exerts remarkable DNA damage after reduction to platinum(II) complex, and up-regulates the expression of p53 and γ-H2AX. Then, complex 2 promotes mitochondria-mediated apoptosis effectively by activating the Bcl-2/Bax/caspase3 pathway. Furthermore, inflammation in tumor tissues is restrained by the suppression of enzymes COX-2, MMP-9, NLRP3 and caspase1, which would favor the inhibition of tumor metastasis. Moreover, compound 2 boosts T-cell immunity by restraining PD-L1 expression, and further improving the density of CD3+ and CD8+ T cells in tumor tissues.
研究领域:
药理学
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肿瘤学
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化疗
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药物开发
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癌症生物学
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免疫学
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Mengxuan Zhang,Xuxiang Zheng,Lanyue Kou,Lizhu Xiao,Huan Cai,Tao Hu,Yujiao Ma,Anyi Chen,Min Zhao
In situ -engineered NU-1000@Gra gives 2.20-fold ECL enhancement via dual paths, surmounting single-component trade-off. • First Zr-MOF/graphene synergistically boosts ECL, lifting quantum yield from 11.89% to 15.69% via excited-state optimization. • TDN strategy enhances stability and anti-interference, enabling PD-L1 + tEV detection with LOD 899.35 particles/mL. • NGTA platform detects NSCLC with 100% sensitivity, 90.91% accuracy, 32.09-fold lower LOD than ELISA for tEV biopsy. Tumor-derived PD-L1 + extracellular vesicles (PD-L1 + tEVs) represent valuable liquid-biopsy biomarkers for non-small-cell lung cancer, whereas their reliable quantification is largely restricted by low abundance and complex matrix interference. Herein, we fabricated an in-situ engineered NU-1000@Graphene (Gra) nanohybrid as a kinetics-efficiency dual-boosted electrochemiluminescence (ECL) emitter to build the N U-1000@ G ra t etrahedral a ptasensor (NGTA). Benefiting from intimate interfacial coupling, Gra acted as a bifunctional accelerator in the NU-1000/S 2 O 8 2− system, accelerating interfacial electron transfer and sulfate radical production to realize a 1.58-fold improvement in ECL kinetics and a 1.39-fold enhancement in luminescence efficiency. Assisted by the tetrahedral DNA nanostructure scaffold that suppressed non-specific adsorption, the NGTA achieved an ultralow detection limit of 899.35 particles/mL for PD-L1 + tEVs. Preliminary clinical results demonstrated its diagnostic potential. This work underscores the significance of metal-organic framework (MOF)-Gra interfacial engineering for synergistic ECL amplification, providing a rational material design paradigm for high-performance liquid-biopsy biosensors.
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Acta Biomaterialia
·
2025
·
IF 9.6
Nan Zhong,Ziyue Zu,Yishi Lu,Xuan Sha,Yang Li,Yang Liu,Shangyu Lu,Xi Luo,Yan Zhou,Jun Tao,Feiyun Wu,Zhaogang Teng,Yuxia Tang,Shouju Wang
Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway could effectively initiate antitumor immunity in triple-negative breast cancer. However, current nuclear DNA-mediated activation of STING pathway remains constrained by the tight protection of nuclear membrane and histones, highlighting the need for new strategies to enhance its efficacy. Mitochondrial DNA (mtDNA), in contrast, is more vulnerable to damage. Herein, our nanoplatforms exploited the high glutathione (GSH) environment characteristic of tumors to release abundant Mn 2+ , which induced mitochondrial dysfunction and the release of endogenous mtDNA. The released mtDNA, in conjunction with Mn 2+ itself functioning as a strong cGAS agonist, effectively activated cGAS-STING pathway. Consequently, the cGAS-STING-dependent secretion of type I interferon successively enhanced the maturation of dendritic cells and cross-priming of CD8 + T cells. In a poorly immunogenic 4T1 tumor model, TPP-MMONs efficiently primed systemic antitumor immunity and significantly enhanced the therapeutic efficacy of αPD-L1 therapy, suppressing tumor growth in both localized and metastatic tumor models. These findings provided an innovative and straightforward strategy to enhance TNBC immunogenicity by targeting mitochondrial damage to induce mtDNA-mediated cGAS-STING activation, thereby sensitizing tumors to immune checkpoint inhibitor therapy. Statement of Significance The cGAS-STING pathway is a promising target for overcoming immunoresistance in TNBC. However, current nuclear DNA-based activation strategies are limited by the tight protection of nuclear membrane and histones. Herein, we reported novel manganese-rich, mitochondria-targeting nanoplatforms (TPP-MMONs), which can release abundant Mn²⁺ and significantly induce mitochondrial dysfunction, leading to the release of mtDNA. As a result, the nanoplatforms can effectively stimulate the cGAS-STING pathway, thereby enhancing immune responses and improving the therapeutic efficacy of αPD-L1 therapy, offering new insights into TNBC treatments.
研究领域:
肿瘤学
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免疫学
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纳米医学
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BIOSENSORS & BIOELECTRONICS
·
2023
·
IF 12.6
Zhijun Lin,Mengyao Liu,Wei Xing,Feng-Hua Wang,Hongxia Zhang,Xiao-Li Wei,Hans Schmitthenner,Xi Xie,Xiaojun Xia,Jiang Yang
Sensitive and accurate biomarker-driven assay guidance has been widely adopted to identify responsive patients for immune checkpoint blockade (ICB) therapy to impede disease progression and extend survival. However, most current assays are invasive, requiring surgical pathology specimens and only informing monochronic information. Here, we report a multiplexed enhanced fluorescence microarray immunoassay (eFMIA) based on a nanostructured gold nanoisland substrate (AuNIS), which macroscopically amplifies near-infrared fluorescence (NIRF) of a structurally symmetric IRDye78 fluorophore by over two orders of magnitude of 202.6-fold. Aided by non-contact piezo-driven micro-dispensing (PDMD), eFMIA simultaneously and semi-quantitatively detected intracellular and secreted programmed death-ligand 1 (PD-L1) and intercellular adhesion molecule-1 (ICAM-1) in human nasopharyngeal carcinoma (NPC) cells. The assay performance was superior to fluorescence immunoassays (FIA) and enzyme-linked immunosorbent assays (ELISA), with lower detection limits. Using eFMIA, we found significantly differential levels of soluble PD-L1 (sPD-L1) and sICAM-1 in the sera of 28 cancer patients, with different clinical outcomes following anti-PD-1 ICB therapy. With a well-characterized mechanism, the high-performance plasmonic multiplexed assay with the composite biomarkers may be a valuable tool to assist clinicians with decision-making and patient stratification to afford predictive ICB therapy responses.
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Coatings
·
2023
·Vol. 13
·期 8
·1400
·
IF 3.4
Yuyan Peng,Li Jiang,Yifan Li,Xiaoping Yu
Soluble programmed death-ligand 1 (sPD-L1) levels vary widely among different stages of tumor development, so the direct quantification of sPD-L1 as a cancer biomarker is useful in cancer diagnosis, prognosis and therapeutic assessment. There is an urgent need for an sPD-L1 detection method with a broad detection range and high sensitivity for monitoring cancer progression and evaluating the effectiveness of immunotherapy in real time. Herein, we have reported an enzyme-free, label-free surface plasmon resonance imaging (SPRi) sensor based on an aptamer/sPD-L1/anti–PD-L1 sandwich structure with gold nanoparticle (AuNP) signal enhancement for the ultrasensitive quantitative measurement of sPD-L1 for the first time. The gold chip of the SPRi sensing platform was modified by DNA aptamers, sPD-L1 was specifically adsorbed on the surface of a DNA aptamer-modified gold chip and then coupled with anti–PD-L1. Thus, the detection of sPD-L1 at different concentrations was realized through the formation of an aptamer/sPD-L1/anti–PD-L1 sandwich structure. We also enhanced the SPR signal via AuNPs to further improve sensor sensitivity. The SPRi sensor is able to measure sPD-L1 within a linear range of 50 pM–10 nM and 100 fM–50 pM, and the minimum detection limit is 19 fM. The sensor is designed to be widely applicable, with better accuracy and reliability for more application scenarios. The prepared SPRi sensor shows great potential in improving the sensitivity of detecting sPD-L1. The proposed method demonstrates the excellent performance of the SPRi sensor and provides a possibility for the establishment of effective clinical assay methods in the future.Keywords:programmed death-ligand 1;surface sandwich assay;DNA aptamer/antibody bioreceptor pair;surface plasmon resonance;tumor biomarker
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MACROMOLECULAR BIOSCIENCE
·
2021
·Vol. 21
·期 6
·2100049
·
IF 4.979
Yingge Shi,Dong Li,Chaoliang He,Xuesi Chen
Combination therapy can be used to enhance the therapeutic response and decrease side effects during cancer treatment. In this study, a system is developed to locally deliver the immune checkpoint blockade antibody targeting programmed death-ligand 1 (anti-PD-L1 or aPD-L1) and doxorubicin (Dox), by an injectable, biocompatible polypeptide hydrogel as a drug depot. The localized and sustained release of Dox after the intratumoral injection of the co-loaded hydrogel induces immunogenic tumor cell death, thus promoting an antitumor immunological response. The tumor inhibitory effect is significantly enhanced by the simultaneous release of aPD-L1 at the tumor site thanks to its action on the inhibition of the PD-1/PD-L1 pathway and restoration of the tumor-killing effect of cytotoxic T cells. Treatment of the B16F10 melanoma model with the aPD-L1 and Dox co-loaded hydrogel leads to a remarkable inhibition of tumor progression and prolongation of animal survival.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-22
·
IF 12.6
Liu Yanhong,Gong Liming,Feng Jing,Xiao Congcong,Liu Chenfei,Chen Bohan,Chen Liqing,Jin Mingji,Guan Youyan,Gao Zhonggao,Huang Wei
Immune checkpoint inhibition (ICI) has become the mainstay of immunotherapy for the treatment of renal cell carcinoma (RCC). However, only a small portion of patients exhibit a positive response to PD-1/PD-L1 blockade therapy and the key reason is that RCC belongs to a vascular-rich tumor for promoting immunosuppression. Specifically, the dysfunctional tumor vasculature hinders effector T cell infiltration and induces immunosuppressive tumor microenvironment via the release of cytokine, which attenuates the therapeutic efficacy of ICI. Therefore, regulating abnormal tumor vasculature may be a promising strategy to overcome the immunosuppressive microenvironment and enhance ICI therapy. Here, we propose an NGR peptide-modified actively targeted liposome (Axi/siRNA PD−L1 @NGR-Lipo) to encapsulate the anti-angiogenic agents Axitinib and PD-L1 siRNA to promote tumor vasculature normalization and relieve immune evasion for enhanced anti-tumor immunotherapy. With NGR-mediated tumor homing and active targeting, Axi/siRNA PD−L1 @NGR-Lipo could act on tumor vascular endothelial cells to inhibit neo-angiogenesis, increase pericyte coverage and vascular perfusion, and normalize the structure and function of tumor blood vessels. Meanwhile, it also enhanced immune effector T cells and NK cells infiltration and reduced the proportion of immunosuppressive T cells including MDSC cells and Tregs, thus improving the tumor immunosuppressive microenvironment. Moreover, Axi/siRNA PD−L1 @NGR-Lipo reduced the expression of PD-L1 protein in tumor cells, restored the recognition and killing ability of cytotoxic T cells, and relieved immune evasion. As expected, Axi/siRNA PD−L1 @NGR-Lipo displayed superior anti-tumor and anti-metastatic efficacy in mice bearing RCC. Overall, this study demonstrated the important potential of regulating abnormal tumor vasculature to reshape the immunosuppressive microenvironment and boost ICI therapy, which represents a promising avenue for the synergistic anti-tumor with cancer immunotherapy. Graphical
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CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Xinyu Zhang,Hui Liu,Chenyu Wang,Yuan Gao,Shiqi Zhao,Mengyao Mu,Ke Ren,Yufang Gong,Qing Fan,Xiao Sun
Biodegradable Two-dimensional (2D) nanomaterials have attracted tremendous interest in biomedical application. Herein, a biodegradable ferrous sulfide nanosheet with ultrathin structure and uniform size was developed. Following its development, the application of the self-enhanced photothermal nanoplatform (FMPN) in vivo by combining Mn-DOTA and dimeric PD-L1 affibody for targeted dual-mode magnetic resonance imaging (MRI) guided synergistic tumor therapy is explored. Dual-contrast enhanced subtraction imaging (DESI) was used to evaluate the excellent T1-T2 MRI ability of FMPN. FMPN displayed excellent photothermal conversion efficiency (η = 40.33 %) and biodegradability, thus had good tumor photothermal therapy effects with good biosafety. In addition, FMPN with pH-responsive Fe 2+ release can effectively induce tumor cell ferroptosis, further intensifying PTT and subsequent immunologic cell death. PD-L1 affibody could endow this nanoplatform with efficient tumor targeting, terminating T cells’ immune suppression by effectively blocking the interaction between PD-1 and PD-L1. Systemic delivery of FMPN significantly inhibited tumor progression in primary, metastatic and abscopal tumors, and showed obvious dual-mode MRI enhancement. Therefore, this nanoplatform exhibited promising potential for MRI-guided synergistic ferroptosis/photothermal/immunotherapy.
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Experimental Hematology & Oncology
·
2025
·Vol. 14
·期 1
·1-17
·
IF 13.5
Ren Xueting,Wu Jinpeng,Li Jing,Zhai Zhen,Li Xiang,Guan Feng,Wang Meng,Ma Xiaobin,Tan Zengqi,Kang Huafeng,Lin Shuai
Background The abundance of PD-L1 on the surface of tumor cells is a critical factor in sensitizing these cells to T cell-mediated immune killing. While abnormal glycosylation of PD-L1 is known to influence its expression and function, the precise regulatory mechanisms remain unclear.Methods This study utilized bioinformatics analysis to explore the role of MGAT3, a key gene involved in the formation of the bisecting GlcNAc structure, in breast cancer (BC). Experimental approaches were employed to increase bisecting GlcNAc levels in BC cells, followed by assessments of PD-L1 expression, CD8+ T cell-mediated cytotoxicity, extracellular vesicle (EV)-associated PD-L1, and PD-L1/PD-1 interaction. Additionally, forskolin, a bisecting GlcNAc agonist, was combined with anti-PD-L1 antibody to evaluate its antitumor effects in vivo.Results MGAT3 was found to be expressed at low levels in BC tissues but positively correlated with CD8+ T cell infiltration. Elevating bisecting GlcNAc levels in BC cells significantly enhanced the cytotoxic efficacy of CD8+ T cells. High bisecting GlcNAc modification promoted PD-L1 degradation via the lysosomal pathway, reducing PD-L1 expression and its binding to PD-1. Furthermore, increased bisecting GlcNAc levels reduced PD-L1 in tumor cell-derived EVs, impairing the EVs’ ability to block CD8+ T cells and indirectly enhancing T cell cytotoxicity. The combined use of forskolin and anti-PD-L1 antibody significantly increased CD8+ T cell abundance and activity, achieving a more effective antitumor response in vivo.Conclusion sThese findings demonstrate that enhancing bisecting GlcNAc modification in BC cells promotes PD-L1 degradation and inhibits its binding to PD-1, thereby boosting CD8+ T cell-mediated cytotoxicity, providing a promising strategy for immune modulation in BC therapy.
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Materials Today Bio
·
2026
·
IF 11
Jukai Feng,Yuting Zhang,Wenhan Liu,Pu Zhang,Jianbin Xiao,Qiang Feng,Zhiyu Wang,Jinyu Zhang,Yang Zhong,Zhongying Shi,Meiqi Pan,Xiaolong Zhang,Jingfeng Liu,Jianmin Wang
The combination of atezolizumab (T, anti-PD-L1) and bevacizumab (A, anti-VEGF) (“T+A”) are recommended as first line treatment in patients with unresectable hepatocellular carcinoma (HCC). However, there is a lack of reliable methods to accurately screen beneficiary populations and predict therapeutic outcomes for “T+A” treatment. In this study, we developed two antibody-labelled quantum dot (QD)-based nanoprobes with non-overlapping near-infrared II (NIR-II) fluorescence for simultaneous in vivo imaging of VEGF and PD-L1 levels within tumors. These nanoprobes utilized NIR-II QDs (emission: ∼950 nm and 1550 nm) as cores, while coating with 4-Arm-PEG-NH 2 as a linker to accomplish highly efficient conjugation of anti-VEGF or anti-PD-L1 antibodies via amide condensation. By using tumor-bearing mouse model, we confirmed positive correlation between the in vivo fluorescence signal and the corresponding protein expression level of tumors as determined by immunohistochemistry. Importantly, our results demonstrated that high fluorescence signal of VEGF and PD-L1 levels within tumors indicated more immunosuppressive microenvironment and was associated with faster tumor progression. At meanwhile, fluorescent imaging for VEGF and PD-L1 levels before treatment could predict the endpoint of therapeutic response to “T+A” regimen. Indeed, high fluorescence signal suggested a better therapeutic response versus that with low fluorescence. Overall, our findings established an in vivo dual-targets fluorescent molecular imaging technique as a promising clinical decision-making tool that can predict response to “T+A” regimen in a minimally invasive manner prior to treatment initiation, therapy enabling personalized therapy selection for patients with advanced HCC.
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JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 7.446
Yiqiang OuYang,Jian Gao,Lei Zhao,Junfeng Lu,Haiqing Zhong,Hua Tang,Shuanglong Jin,Lu Yue,Yuezhen Li,Wenjie Guo,Qiang Xu,Yisheng Lai
Two series of novel o-(biphenyl-3-ylmethoxy)nitrophenyl compounds (A1–31 and B1–17) were designed as programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors. All compounds showed significant inhibitory activity with IC50 values ranging from 2.7 to 87.4 nM except compound A17, and compound B2 displayed the best activity. Further experiments showed that B2 bound to the PD-L1 protein without obvious toxicity in Lewis lung carcinoma (LLC) cells. Furthermore, B2 significantly promoted interferon-gamma secretion in a dose-dependent manner in vitro and in vivo. Especially, B2 exhibited potent in vivo anticancer efficacy in an LLC-bearing allograft mouse model at a low dose of 5 mg/kg, which was more active than BMS-1018 (tumor growth inhibition rate: 48.5% vs 17.8%). A panel of immunohistochemistry and flow cytometry assays demonstrated that B2 effectively counteracted PD-1-induced immunosuppression in the tumor microenvironment, thereby triggering antitumor immunity. These results indicate that B2 is a promising PD-1/PD-L1 inhibitor worthy of further development.
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