JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-22
·
IF 10.2
Zhang Shushan,Huang Yongquan,Pi Songying,Chen Hui,Ye Feile,Wu Chaoqun,Li Liujun,Ye Qing,Lin Yuhong,Su Zhongzhen
Incomplete radiofrequency ablation (IRFA) triggers mild protective autophagy in residual tumor cells and results in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and causes resistance to anti-PD-1/PDL1 therapy, which bringing a great clinical challenge in residual tumors immunotherapy. Mild autophagy activation can promote cancer cell survival while further amplification of autophagy contributes to immunogenic cell death (ICD). To this regard, we constructed active targeting zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) loaded with STF62247 or both STF62247 and BMS202, namely STF62247@ZIF-8/PEG-FA (SZP) or STF62247-BMS202@ZIF-8/PEG-FA (SBZP) NPs. We found that SZP NPs inhibited proliferation and stimulated apoptosis of residual tumor cells exposed to sublethal heat stress in an autophagy-dependent manner. Further results discovered that SZP NPs could amplify autophagy in residual tumor cells and evoke their ICD, which dramatically boosted the maturation of dendritic cells (DCs). Through vaccination experiments, we found for the first time that vaccination with heat + SZP treatment could efficiently suppress the growth of new tumors and establish long-term immunological memory. Furthermore, SBZP NPs could remarkably promote the ICD of residual tumor cells, obviously activate the anti-tumor immune microenvironment, and significantly inhibit the growth of residual tumors. Thus, amplified autophagy coupled with anti-PD-1/PDL1 therapy is potentially a novel strategy for treating residual tumors after IRFA.Graphical Abstract
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SENSORS AND ACTUATORS B-CHEMICAL
·
2023
·
IF 8.4
Ruhui Hu,Suyun Zhong,Hezhen Liu,Yawen Liu,Hongxia Chen,Xiaojun Hu
A dual-ligand Cu-MOFs (Cu-F/Hs) based on phenylalanine (Phe) and histidine (His) was innovatively constructed with enhanced catalytic property. Among them, Phe can interact with the dopamine (DA) to enhance the substrate affinity. Meanwhile, the coordination of His with copper ions was inspired by the active site structure of natural laccase to improve the catalytic activity. The K m value of Cu-F/Hs was 0.14 times of laccase, indicating a high affinity for the catalytic substrate DA. Accordingly, a sensitive sensor for PD-L1 detection was designed by using Cu-F/Hs, which can catalyze DA to form redox-active polymeric conjugates deposited on the electrode surface with good electrical conductivity, thereby contributing a “signal-down” electrochemical response with a double signal enhancement. The detection limit was 0.12 ng/mL in the detection range of 0.5 – 200 ng/mL. This work provided a new and simple way to synthesize MOFs with high substrate affinity and efficient activity, and a general signal amplification strategy induced by the catalytic deposition.
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BIOMATERIALS
·
2020
·
IF 10.317
Changrong Wang,Xiaoguang Shi,Huijuan Song,Chuangnian Zhang,Xiaoli Wang,Pingsheng Huang,Anjie Dong,Yumin Zhang,Deling Kong,Weiwei Wang
Immunotherapy has revolutionized cancer treatment; however, only a limited portion of patients show responses to currently available immunotherapy regimens. Here, we demonstrate that RNA interference (RNAi) combined with immunogenic chemotherapy can elicit potent antitumor immunity against melanoma. Specially, we developed cationic polymer-lipid hybrid nanovesicles (P/LNVs) as a new delivery system for doxorubicin and small interfering RNA (siRNA) with extensive cytotoxicity and gene silencing efficiency towards B16 cells. The deployment of doxorubicin-loaded P/LNVs augmented the expression and presentation of endogenous tumor antigens directly in situ by inducing the immunogenic cell death of B16 cells through poly(ADP-ribose) polymerase 1-dependent (PARP1) apoptosis pathway; thereby, eliciting remarkable antitumor immune responses in mice. Leveraging dying B16 cells as a vaccination strategy in combination with RNAi-based programmed cell death ligand 1 (PD-L1) knockdown showed efficacy in both prophylactic and metastasis melanoma settings. Strikingly, PD-L1 blockade synergized with a sub-therapeutic dose of doxorubicin triggered robust therapeutic antitumor T-cell responses and eradicated pre-established tumors in 30% of mice bearing B16 melanoma. Our findings indicated that this combination treatment provided a new powerful immunotherapy modality, characterized by markedly increased infiltration of effector CD8 + T cells and effective alleviation of the immunosuppressive microenvironment in tumors. P/LNVs is a versatile and highly scalable carrier that can enable a broad combination of nanomedicine and RNAi, providing new therapeutic strategies for advanced cancers.
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Biomaterials Science
·
2019
·Vol. 8
·期 5
·1418-1430
·
IF 5.251
Tiankuan Li,Zhongqian Hu,Chao Wang,Jian Yang,Chuhui Zeng,Rui Fan,Jinhe Guo
Immunotherapy is gradually becoming as important as traditional therapy in the treatment of cancer, but adverse drug reactions limit patient benefits from PD1/PD-L1 checkpoint inhibitor drugs in the treatment of non-small cell lung cancer (NSCLC). As a chemotherapeutic drug for NSCLC, docetaxel (DTX) can synergize with PD1/PD-L1 checkpoint inhibitors but increase haematoxicity and neurotoxicity. Herein, anti-PD-L1 monoclonal antibody (mAb)-conjugated and docetaxel-loaded multifunctional lipid-shelled microbubbles (PDMs), which were designed with biologically safe phospholipids to produce synergistic antitumour effects, reduced the incidence of side effects and promoted therapeutic effects under ultrasound (US) irradiation. The PDMs were prepared by the acoustic-vibration method and then conjugated with an anti-PD-L1 mAb. The material features of the microbubbles and their cytotoxic effects, cellular apoptosis and cell cycle inhibition were studied. A subcutaneous tumour model was established to test the drug concentration-dependent and antitumour effects of the PDMs combined with US irradiation, and an orthotopic lung tumour model simultaneously confirmed the antitumour effect of this synergistic treatment. The PDMs achieved higher cellular uptake than free DTX, especially when combined with US irradiation. The PDMs combined with US irradiation also induced an increased rate of cellular apoptosis and an elevated G2-M arrest rate in cancer cells, which was positively correlated with PD-L1 expression. An in vivo study showed that synergistic treatment had relatively strong effects on tumour growth inhibition, increased survival time and decreased adverse effect rates. Our study possibly provides a well-controlled design for immunotherapy and chemotherapy and has promising potential for clinical application in NSCLC treatment.
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ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Mingli Ye,Lihua Mou,Jianzhou Feng,Lingling Wu,Dangqin Jin,Xiaoya Hu,Qin Xu,Yun Shu
Tumor-derived extracellular vesicles (T-EVs) PD-L1 are an important biomarker for predicting immunotherapy response and can help us understand the mechanism of resistance to immunotherapy. However, this is due to the interference from a large proportion of nontumor-derived EVs. It is still challenging to accurately analyze T-EVs PD-L1 in complex human fluids. Herein, a simple and ultrasensitive method based on the dual-aptamer-proximity ligation assay (PLA)-guided rolling circle amplification (RCA) for the analysis of T-EVs PD-L1 was developed. First, dual aptamers with strong binding affinity were utilized for the recognition of EpCAM and PD-L1 on EVs, and then the aptamer-based PLA occurred. With the aid of the high signal amplification ability of RCA guided by the dual-aptamer-based PLA and efficient magnetic separation, the biosensor could realize highly sensitive quantification of EpCAM and PD-L1 dual-positive EVs with a low detection limit of 7.5 particles/μL. In addition, this method based on the aptamer-PLA-guided RCA was used to discriminate cancer patients from healthy donors with 100% accuracy without additional purification. Overall, this strategy might provide a practical tool for the analysis of multiple proteins on EVs, exhibiting great potential in early cancer diagnosis and treatment.
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JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Qing-Hua Shen,Long-Bo Yu,Shan-Ming Yao,Zhi-Yuan Li,Qi-Qi Zhang,Peng Wang,Cai-Ping Tan
Metalloenzyme mimics based on small molecules are valuable therapeutic candidates, but there are few reports on their mechanism of action. Inspired by natural enzymes, we designed two Cu–Fe bimetallic multienzyme mimetics (CuFc1 and CuFc2). Due to the coordination of the bimetallic centers, CuFc1 exhibits mimetic activities for multiple enzymes, including peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), and glutathione oxidase (GSHOx). CuFc1 can catalyze cascade reactions from •O2– and H2O2 to O2 and •OH, which leads to a storm of reactive oxygen species and causes cuproptosis and ferroptosis in cancer cells simultaneously. As CuFc1 treatment upregulates the expression of PD-L1, it acts synergistically with the PD-L1 inhibitor (BMS-1) to remodel the tumor immune microenvironments and stimulates intense anticancer immune responses in vivo. In summary, through reasonable molecular design, we first demonstrate the enormous potential of metallo small molecule-based multienzyme mimics in cancer immunotherapy.
研究领域:
生物无机化学
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癌症生物学
·
免疫治疗
·
酶学
·
金属药物
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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
·
诊疗学
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Biomaterials Science
·
2022
·Vol. 10
·期 5
·1292-1303
·
IF 7.59
Zian Wang,Xuan Wang,Hua Yu,Meiwan Chen
Camptothecin (CPT) is a potent broad-spectrum antitumor agent with efficient therapeutic effect for various cancers. However, its application in glioma therapy has been impeded by the tumor immunosuppressive environment and blood–brain barrier (BBB)-associated drug delivery challenges. Herein, neurotransmitter analogs-modified liposomes (NTs-LIP) were prepared by doping lipidized tryptamine (Tryp) to co-deliver CPT and curcumin (CUR) for improved chemo-immunotherapy in glioma. The introduction of Tryp promotes the delivery efficiency of CPT and CUR across the BBB. CPT inhibits cell proliferation after cellular uptake of NTs-LIP, the combination of which with CUR downregulates the elevated expression of the programmed cell death 1 ligand 1 (PD-L1) caused by CPT to prevent the inactivation of T-cells and synergistically enhance chemo-immunotherapy efficacy. Furthermore, both Tryp and CUR interfere with the indoleamine 2,3-dioxygenase (IDO) pathway to reduce regulatory T cell (Treg)-mediated immunosuppression, exhibiting the potential to combine with PD-L1 inhibition for synergistic antitumor immunity. Taken together, this platform contributes towards targeted delivery and alleviation of the immunosuppressive environment in glioma therapy.
研究领域:
药理学
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神经科学
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肿瘤学
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纳米技术
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免疫疗法
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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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Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Chaoyan Yao,Lei Wang,Weidong Liu,Ning Shi,Ziling Liao,Yuxuan Fu,Jinhao Ouyang,Xuan Lei,Qianping Huang,Siyu Li,Yihua Zhouyang,Pinnan Zhao,Jie Wang,Hongjuan Xu,Wenhu Zhou,Xingjun Jiang,Xiang Gao,Caiping Ren,Longlong Luo
The effective treatment of nasopharyngeal carcinoma (NPC) is challenged by an immunosuppressive tumor microenvironment (TME) and insufficient immune effector cell activation. Herein, we design a synergistic tri-modal therapeutic strategy to overcome these barriers. This platform integrates: (1) a CD109-targeted liposomal doxorubicin (S3-Lip-DOX) for precise chemotherapy and induction of immunogenic cell death (ICD); (2) non-genetically engineered natural killer (NK) cells armed with dual aptamers (targeting CD109 and PD-L1) via bio-orthogonal chemistry for enhanced tumor recognition (S3-P-NK); and (3) an Fc-engineered anti-PD-L1 antibody (Atezolizumab/IgG1) that restores antibody-dependent cellular cytotoxicity (ADCC). Crucially, we uncovered a key mechanistic synergy: S3-Lip-DOX treatment, as a stress-adaptive response, upregulates PD-L1 expression on NPC cells. This finding provides a compelling rationale for the integration, turning a potential immune escape mechanism into a therapeutic vulnerability. The complete regimen, comprising S3-Lip-DOX, S3-P-NK, and Atezolizumab/IgG1, demonstrated potent synergistic antitumor effects in vitro and in vivo . This triple-combination therapy not only achieved significant tumor regression but also robustly reprogrammed the innate tumor microenvironment, evidenced by enhanced dendritic cell (DC) maturation and pro-inflammatory macrophage activation. This work establishes a mechanism-driven, modular therapeutic platform that effectively coordinates targeted chemotherapy with innate immunotherapy, holding significant translational potential for solid tumors.
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MOLECULAR PHARMACEUTICS
·
2026
·
IF 4.5
Wanyu Jin,Shujun Xu,Hongyan Zhang,Yujie Li,Mengna Shi,Ninghui Ma,Xin Zhang,Lujia Zhu,Yang Xiong
The limited efficacy of programmed death-ligand-1 (PD-L1) monoclonal antibodies (aPD-L1) in triple-negative breast cancer (TNBC) is largely attributable to the immunosuppressive tumor microenvironment (TME). Notably, the abundance of cancer-associated adipocytes (CAAs) constitutes a distinctive feature of the TNBC microenvironment, contributing significantly to its immunosuppressive nature. CAAs upregulate cluster of differentiation 36 (CD36), a fatty acid translocase on tumor cells, thereby promoting excessive fatty acids (FAs) uptake and lipid droplet (LD) accumulation, which starve immune cells and reinforce immunosuppression through this metabolic adaptation. Berberine (BBR), a bioactive alkaloid derived from Rhizoma coptidis, has previously been shown to ameliorate lipid metabolism disorders through downregulation of CD36 in metabolic diseases such as hepatic steatosis. We therefore hypothesize that BBR inhibits CD36-mediated FAs uptake and reduces LD accumulation in tumor cells, representing a novel mechanism that remains unexplored in the context of TNBC. In this study, we demonstrated that BBR counteracts the tumor-promoting effects of CAAs in 4T1 cells by inhibiting CD36 upregulation and its mediated FAs uptake, thereby reducing CAA-induced LD accumulation and ultimately suppressing tumor cell proliferation. Furthermore, BBR remodeled the TME by enhancing CD8+ T cell recruitment and activity, while reducing immunosuppressive factors. In order to improve the sustained release of BBR at the tumor site and overcome its poor aqueous solubility, we created a thermosensitive hydrogel-based nanoparticle system (BBR-NPs-GEL). This injectable hydrogel demonstrated favorable thermosensitive gelation and shear-thinning behavior, making it suitable for localized administration. It exhibited a gelation temperature of 35.3 ± 0.2 °C and a sustained release profile with 52% of BBR released within 48 h. In 4T1Fluc tumor-bearing mice, BBR-NPs-GEL significantly suppressed tumor growth and remodeled the TME, as evidenced by increased infiltration of CD8+ T cells (+8.49%), activation of dendritic cells (+8.39%), and a shift toward M1-macrophages (+39.9%), accompanied by a reduction in M2-macrophages (−19.13%). Importantly, when combined with aPD-L1 therapy, the treatment elicited synergistic antitumor effects, resulting in enhanced tumor regression. This combination strategy effectively overcame metabolic immunosuppression and reversed immune resistance in TNBC.
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JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Xin Yang,Wanqiong Li,Shuzhen Li,Shaomeng Chen,Zheng Hu,Zhuoying He,Xueqin Zhu,Xiaoshuang Niu,Xiuman Zhou,Huihao Li,Youmei Xiao,Juan Liu,Xinghua Sui,Guanyu Chen,Yanfeng Gao
Peptide immune checkpoint inhibitors in cancer immunotherapy have attracted great attention recently, but oral delivery of these peptides remains a huge challenge due to the harsh gastrointestinal environment, large molecular size, high hydrophilic, and poor transmembrane permeability. Here, for the first time, a fish oil-based microemulsion was developed for oral delivery of programmed death-1/programmed cell death-ligand 1 (PD-1/PD-L1) blocking model peptide, OPBP-1. The delivery system was characterized, in vitro and in vivo studies were conducted to evaluate its overall implication. As a result, this nutraceutical microemulsion was easily formed without the need of co-surfactants, and it appeared light yellow, transparent, good flowability with a particle size of 152 ± 0.73 nm, with a sustained drug release manner of 56.45 ± 0.36% over 24 h and a great stability within the harsh intestinal environment. It enhanced intestinal drug uptake and transportation over human intestinal epithelial Caco-2 cells, and drastically elevated the oral peptide bioavailability of 4.1-fold higher than that of OPBP-1 solution. Meanwhile, the mechanism of these dietary droplets permeated over the intestinal enterocytic membrane was found via clathrin and caveolae-mediated endocytic pathways. From the in vivo studies, the microemulsion facilitated the infiltration of CD8 + T lymphocytes in tumors, with increased interferon-γ (IFN-γ) secretion. Thus, it manifested a promising immune anti-tumor effect and significantly inhibited the growth of murine colonic carcinoma (CT26). Furthermore, it was found that the fish oil could induce ferroptosis in tumor cells and exhibited synergistic effect with OPBP-1 for cancer immunotherapy. In conclusion, this fish oil-based formulation demonstrated great potential for oral delivery of peptides with its natural property in reactive oxygen species (ROS)-related ferroptosis of tumor cells, which provides a great platform for functional green oral delivery system in cancer immunotherapy.
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