CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yanzhu Wang,Linghe Zang,Liyuan Guan,Xihang Ren,Zongmin Xia,Zhou Li,Zhaoxu Meng,He Lian
The efficacy of αPD-L1, an immune checkpoint inhibitor, in the treatment of melanoma is limited by individual patient variations and tumor immunosuppressive cells. Consequently, current immunotherapy of melanoma is far from satisfactory. In this study, bispolyphenol nanoparticles (Phl-CaCO 3 @Lut-Cu NPs) were constructed by wrapping a luteolin-copper (Lut-Cu) network around the surface of phloretin-loaded calcium carbonate (Phl-CaCO 3 ) nanoparticles. Upon entering tumor cells, Phl-CaCO 3 @Lut-Cu nanoparticles efficiently released Cu 2+ , phloretin (Phl), and luteolin (Lut) due to the acid-responsive properties of calcium carbonate and the metal-phenolic network. The copper ions mediated cuproptosis by binding to dihydrolipoamide acetyltransferase and induced cellular immune responses by promoting release of damage-associated molecular patterns (DAMPs). In addition, Phl blocked glucose transport by inhibiting glucose transporter 1 activity, thereby disrupting the energy supply process in tumor cells. Simultaneously, Lut inhibited expression of hypoxia-inducible factor-1α, negatively regulating aerobic glycolysis. This study aimed to reshape the tumor microenvironment by exploring the synergistic effects of cuproptosis and dual glycolysis inhibition, enhancing the T cell-mediated immune response, and suppressing tumor cell growth when combined with αPD-L1. This study provides a new perspective and strategy for melanoma immunotherapy.
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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药理学
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产品关联
DOI
高影响因子
Advanced Science
·
2026
·
IF 14.1
Tingting Zhang,Mengyi Xu,Yan Zhang,Zhiwen Li,Danqing Song,Jing Pang,Ke Li,Yanxiang Wang
Bacterial-based materials, leveraging their inherent hypoxia and immunosuppressive microenvironment-targeting capabilities, immunomodulatory effects, and drug delivery advantages, have emerged as promising strategies to modulate the tumor microenvironment (TME) for converting immunologically “cold” tumors into “hot” ones. This study innovatively functionalizes Lactobacillus reuteri ( L. reuteri ) using metal-phenolic networks (MPNs) to co-deliver αPD-L1 antibodies and gallium ions (Ga 3 + ) for synergistic anti-tumor therapy. The MPN coating materials enable pH-responsive drug release, whereby αPD-L1 reverses immunosuppression and Ga 3 + disrupts tumor iron metabolism, mimicking Fe 3 + to induce selective ferroptosis. In vivo evaluations in B16 and LLC tumor-bearing mouse models revealed that functionalized L. reuteri had the potential to reprogram the tumor immune microenvironment and significantly enhanced tumor regression. This system achieved multifunctional tumor regression in vivo, integrating bacterial hypoxia-driven chemotaxis, MPN-mediated ferroptosis, and immune checkpoint inhibitors (ICIs)-driven immune activation. Thus, the multifunctional materials offer a novel strategy for treating refractory or immunologically “cold” tumors.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2025
·Vol. 44
·期 1
·1-25
·
IF 12.8
Wang Pengyu,Guo Weihua,Liu Shuyue,Li Shouyi,Li Jiaqi,Ding Bowen,Yin Fengyi,Yang Yang,Li Xingjiang,Cao Pei,Ma Chaozhe,Zhang Wanying,Song Yidan,Geng Yating,Liu Lantao,Hu Jing,Hao Jihui,Feng Yukuan
Background Copper accumulation triggers mitochondrial-driven cell death, known as cuproptosis, offering a promising mechanism for targeted cancer therapy. Recent studies have highlighted the critical role of intratumoral copper levels in regulating the expression of programmed cell death ligand-1 (PD-L1), suggesting that copper-induced cuproptosis not only enhances cancer cell death but may also amplify the effects of anti-PD-L1 antibodies (αPD-L1). However, in tumors where monotherapy with αPD-L1 shows limited efficacy, particularly in pancreatic ductal adenocarcinoma (PDAC), the role of copper-induced cuproptosis in enhancing αPD-L1 treatment efficacy and its underlying mechanisms remain unclear. Meanwhile, inadequate tumor drug accumulation and glycolysis significantly restrict the efficacy of cuproptosis. To address these challenges, we have synthesized a novel nanozyme, Pt@PCN-Cu, designed to stabilize intracellular copper accumulation and effectively induce cuproptosis. Additionally, we aim to determine whether this strong induction of cuproptosis can synergize with αPD-L1 to enhance cancer therapy, ultimately paving the way for novel strategies to improve PDAC treatment. Methods Pt@PCN-Cu was synthesized via a one-pot method, and its therapeutic potential was assessed in combination with αPD-L1 for the treatment of PDAC. Initially, the material’s properties were characterized, and its efficient cellular uptake was confirmed. Anti-tumor efficacy was evaluated by inducing cuproptosis in PDAC cell lines and xenograft models. RNA sequencing (RNA-seq) was utilized to identify key regulators involved in the modulation of PD-L1 expression by cuproptosis. Lastly, the therapeutic efficacy of Pt@PCN-Cu combined with αPD-L1 was evaluated in vivo, focusing on tumor growth inhibition and immune modulation within the tumor microenvironment (TME). Results Pt@PCN-Cu demonstrates excellent physicochemical properties and remarkable cascade catalytic activity, providing a solid foundation for further in vitro and in vivo studies. In vitro, Pt@PCN-Cu efficiently transports copper and induces cuproptosis primarily through mitochondrial dysfunction. Mechanistic studies show that Pt@PCN-Cu triggers the dissociation of hexokinase 2 (HK2) from mitochondria, leading to a reduction in HK2 activity. This decline in HK2 activity impairs glycolysis, a metabolic pathway essential for tumor energy metabolism, which in turn results in elevated PD-L1 levels. In vivo, Pt@PCN-Cu demonstrates excellent safety and accumulates at the tumor site in a subcutaneous PDAC mouse model, inducing cuproptosis. Moreover, the combination of Pt@PCN-Cu with αPD-L1 further enhanced its therapeutic efficacy and effectively reprogrammed the immunosuppressive TME. Conclusion This study presents strong evidence confirming the safety and therapeutic potential of Pt@PCN-Cu in PDAC treatment. Importantly, Pt@PCN-Cu not only induces cuproptosis but also significantly enhances antitumor efficacy in combination with αPD-L1 by regulating PD-L1 expression through HK2 modulation. These findings underscore a more effective and innovative approach for treating PDAC.
研究领域:
肿瘤学
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分子生物学
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免疫学
·
纳米医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Sheng Ma,Haochen Yao,Xinghui Si,Zichao Huang,Ruoyi Wang,Renming Wan,Zhaohui Tang,Guoqing Wang,Wantong Song
Reversing the aggravated immunosuppression hence overgrowth of colorectal cancer (CRC) caused by the gut inflammation and microbiota dysbiosis is pivotal for effective CRC therapy and metastasis inhibition. However, the low delivery efficiency and severe dose-limiting off-target toxicities caused by unsatisfied drug delivery systems remain the major obstacles in precisely modulating gut inflammation and microbiota in CRC therapy. Herein, a multifunctional oral dextran-aspirin nanomedicine (P3C-Asp) was utilized for oral treatment of primary CRC, as it could release salicylic acid (SA) while scavenging reactive oxygen species (ROS) and held great potential in modulating gut microbiota with prebiotic (dextran). Oral P3C-Asp retained in CRC tissues for over 12 h and significantly increased SA accumulation in CRC tissues over free aspirin (10.8-fold at 24 h). The enhanced SA accumulation and ROS scavenging of P3C-Asp cooperatively induced more potent inflammation relief over free aspirin, characterized as lower level of cyclooxygenase-2 and immunosuppressive cytokines. Remarkably, P3C-Asp promoted the microbiota homeostasis and notably increased the relative abundance of strengthening systemic anti-cancer immune response associated microbiota, especially lactobacillus and Akkermansia to 6.66- and 103- fold over the control group. Additionally, a demonstrable reduction in pathogens associated microbiota (among 96% to 79%) including Bacteroides could be detected. In line with our findings, inflammation relief along with enhanced abundance of lactobacillus was positively correlated with CRC inhibition. In primary CRC model, P3C-Asp achieved 2.1-fold tumor suppression rate over free aspirin, with an overall tumor suppression rate of 85%. Moreover, P3C-Asp cooperated with αPD-L1 further reduced the tumor weight of each mouse and extended the median survival of mice by 29 days over αPD-L1 alone. This study unravels the synergistic effect of gut inflammation and microbiota modulation in primary CRC treatment, and unlocks an unconventional route for immune regulation in TME with oral nanomedicine.
研究领域:
肿瘤学
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药剂学
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免疫学
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微生物学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Xianya Qin,Hongbo Xu,Siyu Zhao,Li Kong,Conglian Yang,Zhiping Zhang
Inspired by the application of organisms as bioreactors in developing drug delivery systems, the living organisms that have undergone biosynthesis are expected to further expand their application scenarios in biomedical domain. Herein, a whole tumor cell vaccine, named as Au@Cell, was developed by harnessing tumor cells as bioreactors to achieve the reduction of chloroauric acid in a mild aqueous phase system within 24 h. The biogeneration process in tumor cells enabled the retention of plenary tumor antigens, enhancement of MHC-I molecules, and generation of innate immune agonist (dsRNA), demonstrating potential for application as a therapeutic cancer vaccine. The resulting cancer vaccine was proved to be non-tumorigenic, revealing favorable in vivo safety. When administrated via intraperitoneal injection, Au@Cell achieved dual-targeting effects on both spleen and peritoneal tumors. Moreover, the combination therapy of Au@Cell and an immune checkpoint inhibitor (αPD-L1) could reprogram the tumor microenvironment by activating CD8 + T cells and effector B lymphocytes, exhibiting favorable anti-tumor effect in MC38 peritoneal carcinomatosis. This study suggested an alternative vaccine manufacturing strategy enabled by the biogeneration process in tumor cells to augment the efficacy against colon cancer-related peritoneal carcinomatosis.
研究领域:
肿瘤学
·
免疫疗法
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生物技术
·
癌症疫苗
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产品关联
DOI
高影响因子
Nanophotonics
·
2021
·Vol. 10
·期 12
·3267-3278
·
IF 8.449
Shanshan Liu,Jiawen He,Ruixiang Song,Mengmeng Zhang,Lianghao Huang,Jing Chen,Meng Wang,Fang Liu,Feifan Zhou
Treatment of pancreatic cancer is faced with great difficulties and challenges due to high lethality and metastasis. Synergism of targeted therapy and immunotherapy has been considered as ideal strategy to both eliminate primary tumors and control metastases. For the treatment of advanced pancreatic cancer, we demonstrated a local photothermal therapy (PTT) following administration of monoclonal antibody of programmed death ligand 1 (αPD-L1). Fe 2 P nanorods were employed as a Fenton agent and photothermal agent, which modified with DSPE-PEG 2000 -Mal for improved biocompatibility and Mal mediated-antigen presentation. Under a low dose laser irradiation at 980 nm, Fe 2 P-PEG-Mal nanorods (NRs) mediated PTT could induce immunogenic tumor cell death that can cause dendritic cells (DCs) infiltration and maturation. In a bilateral pancreatic tumor model, the local treatment of NRs-PTT on primary tumor could cause the increased infiltration of cytotoxic T lymphocytes (CTLs) and decreased residential of M2 macrophages in untreated distal tumors. Furthermore, subsequently intervened αPD-L1 could enhance cell death triggered by CTLs in distal tumors through reversing immunosuppression. An orthotopic pancreatic tumor model was used to further confirm the therapeutic outcome. Finally, the combination of NRs based PTT and αPD-L1 based immunotherapy was able to significantly eliminate orthotopic pancreatic tumors and reduce mesentery metastases. Thus, the strategy may provide a more effective treatment for pancreatic cancer.
研究领域:
肿瘤学
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纳米技术
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免疫疗法
·
生物医学工程
✓ 已验证
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Yunhao Wang,Lei Ding,Ziguo Lin,Baolong Li,Di Hu,Shichen Zhang,Shujun Zhou,Yuxiang Ning,Fei Xin,Yunfei Ying,Fukai Zhu,Peiyuan Wang,Yanfeng Wang
Immune checkpoint inhibitors (ICIs) are among the most prominent immunotherapies for cancer and have been approved as first-line treatments for various tumors. Although some patients experience long-lasting responses, the objective response rate (ORR) of ICIs as monotherapy is relatively low due to the complexity of the tumor microenvironment and the heterogeneity of tumors. Maximizing the benefits of this novel therapeutic approach for a greater number of patients remains a research focus in the field of anticancer treatment. Here, we have investigated a novel Pt/Cu Dual-Atom Nanozyme (Pt/Cu DAzyme) which is engineered by the successive growth of metal-nanocrystals on the assembled surfactant templates. This DAzyme can significantly enhance the intracellular copper ion levels in tumor cells, inducing cuproptosis. Additionally, the Pt/Cu DAzyme exhibits excellent dual enzyme catalytic activity as both glutathione oxidase (GSHOx) and peroxidase (POD) activity, which not only reduces glutathione (GSH) levels in tumors to enhance cuproptosis but also converts intracellular H 2 O 2 into •OH to kill tumor cells. Furthermore, the Pt/Cu DAzyme demonstrates a strong photothermal effect, with its enzymatic reactions being enhanced at mildly elevated temperatures. This DAzyme effectively kills tumors and activates the body’s robust immune system, reshaping the tumor immune-suppressive microenvironment and significantly increasing the therapeutic response rate to αPD-L1. It not only achieves complete ablation of primary tumors but also markedly inhibits the progression of distal tumors and distant metastasis. This study aims to develop new combination therapy strategies to enhance the efficacy of ICIs and promote their advancement in the field of cancer immunotherapy.
研究领域:
癌症免疫疗法
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纳米技术
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肿瘤生物学
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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
ACS Nano
·
2024
·
IF 15.8
Liyun Zheng,Yiming Ding,Shiji Fang,Wenjing Yang,Jiale Chen,Ji Ma,Mengyuan Wang,Jiaoli Wang,Feng Zhang,Xiaoju Guo,Kun Zhang,Gao-Feng Shu,Qiaoyou Weng,Fazong Wu,Zhongwei Zhao,Minjiang Chen,Ji Jiansong
Unfavorable phenotypes characterized by low immunogenicity and acidity within the tumor microenvironment (TME) contribute to immunosuppression and therapeutic resistance. Herein, we rationally synthesized a multifunctional nanoregulator by encapsulating DOX and erianin into calcium carbonate (CaCO3)-based nanoparticles using a modified double emulsion method. The DOX and erianin-loaded CaCO3-based nanoparticles, termed DECaNPs, could effectively induce the calcium overload by triggering calcium influx and absorbing CaCO3 nanoparticles. Additionally, DECaNPs also neutralize the acidic TME by interacting with extracellular protons and limiting lactic acid production, a result of metabolic remodeling in cancer cells. As a result, DECaNPs elicit cellular oxidative stress damage, which mediates the activation of ferroptosis/apoptosis hybrid pathways, and profound immunogenic cell death. Treatment with DECaNPs could inhibit the growth of tumors by promoting oxidative stress, acid neutralization, metabolic remodeling, and protective antitumor immunity in vivo. In addition, DECaNPs could synergistically amplify the antitumor effects of αPD-L1 in a bilateral tumor model by eliciting systemic immune responses. In all, our work presents the preparation of CaCO3-based nanoregulators designed to reverse the unfavorable TME and enhance αPD-L1 immunotherapy through multiple mechanisms.
研究领域:
肿瘤学
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药学
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纳米技术
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免疫学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Shiji Fang,Liyun Zheng,Gao-Feng Shu,Chen Xiaoxiao,Xiaoju Guo,Yiming Ding,Wenjing Yang,Jiale Chen,Zhongwei Zhao,Jianfei Tu,Minjiang Chen,Jian-Song Ji
Immunotherapy is the most promising systemic therapy for hepatocellular carcinoma. However, the outcome remains poor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in altering cell-surface protein levels, potentially undermining the efficacy of immunotherapy against tumors. This highlights its potential as a target for antitumor therapy. Herein, CaCO3-based nanoparticles coencapsulated with DOX, an immunogenic cell death (ICD) inducer, and evolocumab was developed to enhanced the efficacy of immunotherapy. The obtained DOX/evolocumab-loaded CaCO3 nanoparticle (named DECP) exhibits a good capacity of acid neutralization and causes ICD of cancer cells. In addition, DECP is able to evaluate the cell-surface level of MHC-I, a biomarker that correlates positively with patients’ overall survival. Upon intravenous injection, DECP accumulates within the tumor site, leading to growth inhibition of hepa1-6 bearing subcutaneous tumors. Specifically, DECP treatment causes augmented ratios of matured dendritic cells, tumor-infiltrating CD8+ T cells and natural killing cells, while concurrently depleting Foxp3+ regulatory T cells. Peritumoral delivery of DECP enhances the immune response of distant tumors and exhibits antitumor effects when combined with intravenous αPD-L1 therapy in a bilateral tumor model. This study presents CaCO3-based nanoparticles with multiple immunomodulatory strategies against hepatocellular carcinoma by targeting PCSK9 inhibition and modulating immune homeostasis in the unfavorable TME.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Xiaoju Guo,Xiaoxiao Chen,Jiayi Ding,Feng Zhang,Shunyang Chen,Xin Hu,Shiji Fang,Lin Shen,Chenying Lu,Zhongwei Zhao,Jianfei Tu,Gaofeng Shu,Minjiang Chen,Jiansong Ji
Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO 3 by a CaCO 3 -assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.
研究领域:
肿瘤学
·
药理学
·
纳米技术
·
免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Ying Luo,Zhongsheng Xu,Qianying Du,Lian Xu,Yi Wang,Jie Xu,Junrui Wang,Sijin Chen,Wenli Zhang,Bo Liu,Jia Liu,Dajing Guo,Yun Liu
The immune landscape of late-stage liver cancer is featured by severe immunosuppression that is characterized by poor immunogenicity, T-cell exhaustion, and infiltration of a large number of immunosuppressive cells, leading to compromised therapeutic efficacy of mainstream immunotherapies. Herein, we developed a pleiotropic immune cell mobilization strategy to modulate immune systems for immunosuppressive liver cancer therapy. In this study, immunogenic bacteria-derived outer membrane vesicles (OMVs) were exploited as a vector to deposit Cu and Mn with mixed valence states via one-step biomineralization, followed by platelet membrane camouflage, which are denoted as OPCM. Mechanistically, the pleiotropic OPCM possesses POD, CAT, and GPX-like activities, thereby achieving cGAS-STING activation, immunogenic ferroptosis, and tumor hypoxia alleviation, ultimately leading to initiation of the cancer immunity cycle, modulation of both innate and adaptive immune system, and reversion of immunosuppression. Notably, the combination with typical αPD-L1 treatment augmented the tumor suppression effect by amplifying the intensity of ferroptosis due to IFN-γ secretion by activated T cells. Overall, the metal biomineralized OPCMs in combination with αPD-L1 formed a closed-loop therapy that cycles from immunotherapy and ferroptosis therapy, providing new insights for treating immunosuppressive liver cancer.
研究领域:
免疫学
·
癌症生物学
·
生物技术
·
纳米医学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）