Science Bulletin
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2024
·
IF 18.8
Gang Wang,Jingrui Li,Shumin Sun,Yuqi Yang,Zhihui Han,Zifan Pei,Liang Cheng
Excess intracellular H 2 S induces destructive mitochondrial toxicity, while overload of Zn 2+ results in cell pyroptosis and potentiates the tumor immunogenicity for immunotherapy. However, the precise delivery of both therapeutics remains a great challenge. Herein, an electrically activable ZnS nanochip for the controlled release of H 2 S and Zn 2+ was developed for enhanced gas-ionic-immunotherapy (GIIT). Under an electric field, a locality with particularly high concentrations of H 2 S and Zn 2+ was established by the voltage-controlled degradation of the ZnS nanoparticles (NPs). Consequently, the ZnS nanochip-mediated gas-ionic therapy (GIT) resulted in mitochondrial membrane potential depolarization, energy generation inhibition, and oxidative stress imbalance in tumor cells. Interestingly, the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) signaling pathway was activated due to the mitochondrial destruction. Moreover, the released Zn 2+ resulted in the increase of the intracellular Zn levels and cell pyroptosis, which enhanced the immunogenicity via the release of damage-associated molecular patterns (DAMPs). In vitro and in vivo studies revealed that the ZnS nanochip-based GIT effectively eliminated the tumors under an electric field and mobilized the cytotoxic T lymphocytes for immunotherapy. The combination with αCTLA-4 further promoted the adaptive immune response and inhibited tumor metastasis and long-term tumor recurrence. This work presented an electrically activable ZnS nanochip for combined immunotherapy, which might inspire the development of electric stimulation therapy.
研究领域:
癌症治疗
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纳米技术
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免疫学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Science Bulletin
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2025
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IF 21.1
Fangke Zhang,Jiancheng Zheng,Fei Wang,Yaping Zhuang,Yunkai Tang,Juan Wang,Yawei Du,Wei-Li Zhao,Min Lu,Weiguo Hu,Wenguo Cui
Mutations in cytoplasmic DNA-degrading enzymes can lead to the accumulation of cytoplasmic DNA (cytoDNA), which excessively activates DNA-sensing pathways and exacerbates inflammatory aging. Reducing cytoDNA levels to suppress DNA-sensing mechanisms is therefore critical for treating elderly-onset rheumatoid arthritis (EORA). In this study, we constructed Trex1 mRNA loaded lipid nanoparticles (LNPs) via microfluidics and prepared DNase I loaded polydopamine (PDA) nanoparticles through oxidative polymerization. These two components were co-encapsulated into methacrylated hyaluronic acid (HAMA) microspheres using microfluidic photopolymerization. The LNPs incorporate cationic lipids to facilitate mRNA loading and promote endosomal escape, enabling efficient translation of TREX1 and subsequent recognition and degradation of cytoDNA. Meanwhile, cationic mesoporous polydopamine electrostatically adsorbs and degrades extracellular DNA. The microspheres function as a reservoir for sustained nanoparticle release, enabling synergistic inhibition of DNA sensing pathways. This microsphere based vaccine upregulates TREX1 expression in antigen-presenting cells (APCs) and reduces cytoDNA levels, thereby suppressing overactivation of the cGAS-STING signaling axis and promoting immune tolerance. It also attenuates the differentiation of CD4+ T cells into Th1, Th2, Th17, and Treg subsets. In an aged rat model of rheumatoid arthritis, the vaccine alleviated soft tissue swelling, synovitis, and cartilage and bone damage. By clearing excess cytoDNA and restraining DNA-sensing hyperactivation, this vaccine induces cellular immune tolerance and represents a promising therapeutic strategy for rheumatoid arthritis in the elderly.
研究领域:
免疫学
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纳米医学
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分子生物学
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疫苗学
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风湿病学
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衰老研究
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基因治疗
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-19
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IF 10.6
Chen Yang,Tian Hailong,Zhang Xiaodian,Nice Edouard C.,Huang Canhua,Zhang Haiyuan,Zheng Shaojiang
Limited drug accumulation and an immunosuppressive microenvironment are the major bottlenecks in the treatment of glioblastoma multiforme (GBM). Herein, we report a copper-coordination driven brain-targeting nanoassembly (TCe6@Cu/TP5 NPs) for site-specific delivery of therapeutic agents and efficient immunotherapy by activating the cGAS-STING pathway and downregulating the expression of PD-L1. To achieve this, the mitochondria-targeting triphenylphosphorus (TPP) was linked to photosensitizer Chlorin e6 (Ce6) to form TPP-Ce6 (TCe6), which was then self-assembled with copper ions and thymopentin (TP5) to obtain TCe6@Cu/TP5 NPs. This nanoassembly effectively accumulated in tumor sites through the copper transport mechanism. Meanwhile, TCe6@Cu/TP5 could induce mitochondrial impairment by photodynamic therapy (PDT) mediated reactive oxygen species (ROS) accumulation and Cu 2+ triggered cuproptosis, resulting in evoking the AMP-activated protein kinase (AMPK) pathway to degrade PD-L1, and activating the cGAS-STING pathway to enhance anti-tumor immunity. Moreover, TP5 significantly promoted the proliferation and differentiation of dendritic cells (DCs) and T lymphocytes to further amplify the cancer immunity cycle. Collectively, our TCe6@Cu/TP5 NPs effectively facilitate drug accumulation and activate systemic antitumor immunity in vitro and in vivo, providing an innovative solution across the BBB that potentiates GBM immunotherapy. Graphical
研究领域:
癌症研究
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纳米技术
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免疫学
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神经科学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-18
·
IF 14.7
Su Zheng,Xu Dongdong,Hu Xianli,Zhu Wanbo,Kong Lingtong,Qian Zhengzheng,Mei Jiawei,Ma Ruixiang,Shang Xifu,Fan Wenpei,Zhu Chen
Pathogen-host competition for manganese and intricate immunostimulatory pathways severely attenuates the efficacy of antibacterial immunotherapy against biofilm infections associated with orthopaedic implants. Herein, we introduce a spatiotemporal sono-metalloimmunotherapy (SMIT) strategy aimed at efficient biofilm ablation by custom design of ingenious biomimetic metal-organic framework (PCN-224)-coated MnO 2 -hydrangea nanoparticles (MnPM) as a metalloantibiotic. Upon reaching the acidic H 2 O 2 -enriched biofilm microenvironment, MnPM can convert abundant H 2 O 2 into oxygen, which is conducive to significantly enhancing the efficacy of ultrasound (US)-triggered sonodynamic therapy (SDT), thereby exposing bacteria-associated antigens (BAAs). Moreover, MnPM disrupts bacterial homeostasis, further killing more bacteria. Then, the Mn ions released from the degraded MnO 2 can recharge immune cells to enhance the cGAS-STING signaling pathway sensing of BAAs, further boosting the immune response and suppressing biofilm growth via biofilm-specific T cell responses. Following US withdrawal, the sustained oxygenation promotes the survival and migration of fibroblasts, stimulates the expression of angiogenic growth factors and angiogenesis, and neutralizes excessive inflammation. Our findings highlight that MnPM may act as an immune costimulatory metalloantibiotic to regulate the cGAS-STING signaling pathway, presenting a promising alternative to antibiotics for orthopaedic biofilm infection treatment and pro-tissue repair.
研究领域:
生物医学工程
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材料科学
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免疫学
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骨科
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传染病
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产品关联
DOI
PubMed
高影响因子
Nature Communications
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2024
·Vol. 15
·期 1
·1-24
·
IF 14.7
Song Jianwen,Wang He,Meng Xue,Li Wen,Qi Ji
Activatable theranostic systems combining precise diagnosis and robust immune activation have significant potential in cancer treatment. Herein, we develop a versatile nanoplatform integrating hypoxia-activatable molecular imaging with effective photoimmunotherapy for cancer treatment. Our molecular probe features turn-on near-infrared-II (NIR-II) fluorescence and photoacoustic signals in hypoxic tumor environments. It also induces hypoxia-triggered photodynamic and photothermal effects, promoting immunogenic cell death and activating the STING pathway, engaging both innate and adaptive immunity. The molecular probe is formulated with a vascular disrupting agent to amplify the hypoxia-responsive phototheranostic properties, on which M1-like macrophage membrane is camouflaged to shield against premature release while conferring cancer-targeting affinity. The activatable NIR-II fluorescence and photoacoustic imaging enable precise tumor delineation, while the enhanced phototherapy activates tumor-specific cytotoxic T cells, impeding both primary and distant tumor progression and providing protective immunity against rechallenge in 4T1 tumor-bearing female mice. This work advances activatable theranostic protocols for image-guided immunotherapy.
研究领域:
癌症治疗
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医学成像
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免疫学
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纳米技术
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
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IF 9.6
Heying Chen,Xiaomeng Cai,Jiayu Zhang,Hongyan Sun,Jie Zhang,Jun Chen,Zhenglin Yang,Dongqing Wang
Combination of chemotherapy and cancer immunotherapy has shown substantial clinical promise. However, the immunosuppressive tumor microenvironment (TME) poses a critical barrier to this combination therapy. Here, a tumor lysosome-targeted immunomodulatory strategy based on a biomimetic nanoadjuvant is presented, which effectively overcomes the immunosuppressive TME and demonstrates enhanced therapeutic efficacy when combined with chemotherapy. This nanoadjuvant integrates Fe-DOX coordination nanoparticles, a MnCO 3 shell, TLR7/8 agonist (R848), and a mature dendritic cell membrane (DCM) coating. The resulting DCM@(Fe-DOX-Mn-R848) nanoadjuvant induces immunogenic cell death in tumor cells via lysosomal-mitochondrial cascade destruction. Concurrently, it activates the cGAS-STING signaling pathway to promote dendritic cell maturation and repolarize tumor-associated macrophages from M2 to M1 phenotype, thereby effectively enhancing CD8 + T cell activation and tumor therapeutic efficacy. When combined with PD-L1 blockade therapy, the nanoadjuvant demonstrates enhanced efficacy in murine models of primary and recurrent triple-negative breast cancer, establishing durable immune memory. This platform demonstrates significant potential in overcoming immunosuppressive TME and advancing combination therapy through lysosome-targeting drug delivery technology, revealing promising prospects for cancer treatment.
研究领域:
纳米医学
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免疫学
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癌症生物学
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生物工程
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Weichong He,Wei Lv,Linfeng Liu,Yue Gong,Kefan Song,Jiangna Xu,Wei Zhao,Shengnan Li,Zhiyi Min,Qinhua Chen,Jiaqing Yin,Yuqin Chen,Hufeng Fang,Hongliang Xin,Xiangming Fang
Glioblastoma, the most prevalent malignant brain tumor, is a lethal threat to human health, with aggressive and infiltrative growth characteristics that compromise the clinical treatment. Herein, we developed a vitamin D3-inserted lipid hybrid neutrophil membrane biomimetic multimodal nanoplatform (designated as NED@MnO2-DOX) through doxorubicin (DOX)-loaded manganese dioxide nanoparticles (MnO2) which were coated with a vitamin D3-inserted lipid hybrid neutrophil membrane. It was demonstrated that in addition to chemotherapy and chemo-dynamic therapy efficacy, NED@MnO2-DOX exhibited great power to activate and amplify immune responses related to the cGAS STING pathway, bolstering the secretion of type I interferon-β and proinflammatory cytokines, promoting the maturation of DC cells and infiltration of CD8+T cells into the glioma tissue, thereby reversing the immunosuppressive microenvironment of glioma from a “cold” tumor to a “hot” tumor. The biomimetic multimodal nanoplatform has potential as a multimodal strategy for glioma-targeted treatment, especially holding considerable promise for the development of innate immune therapy for glioma.
研究领域:
肿瘤学
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纳米技术
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免疫治疗
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药学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
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2024
·
IF 15.8
Jing Zhang,Yuanwei Pan,Lujie Liu,Yangtao Xu,Chenchen Zhao,Wei Liu,Lang Rao
Immune checkpoint blockade (ICB) has brought tremendous clinical progress, but its therapeutic outcome can be limited due to insufficient activation of dendritic cells (DCs) and insufficient infiltration of cytotoxic T lymphocytes (CTLs). Evoking immunogenic cell death (ICD) is one promising strategy to promote DC maturation and elicit T-cell immunity, whereas low levels of ICD induction of solid tumors restrict durable antitumor efficacy. Herein, we report a genetically edited cell membrane-coated cascade nanozyme (gCM@MnAu) for enhanced cancer immunotherapy by inducing ICD and activating the stimulator of the interferon genes (STING) pathway. In the tumor microenvironment (TME), the gCM@MnAu initiates a cascade reaction and generates abundant cytotoxic hydroxyl (•OH), resulting in improved chemodynamic therapy (CDT) and boosted ICD activation. In addition, released Mn2+ during the cascade reaction activates the STING pathway and further promotes the DC maturation. More importantly, activated immunogenicity in the TME significantly improves gCM-mediated PD-1/PD-L1 checkpoint blockade therapy by eliciting systemic antitumor responses. In breast cancer subcutaneous and lung metastasis models, the gCM@MnAu showed synergistically enhanced therapeutic effects and significantly prolonged the survival of mice. This work develops a genetically edited nanozyme-based therapeutic strategy to improve DC-mediated cross-priming of T cells against poorly immunogenic solid tumors.
研究领域:
癌症研究
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免疫学
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纳米技术
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Han Chen,Haijing Qu,Yuqing Pan,Wei Cheng,Xiangdong Xue
Stimulator of interferon genes (STING) agonists have shown promise in cancer treatment by stimulating the innate immune response, yet their clinical potential has been limited by inefficient cytosolic entry and unsatisfactory pharmacological activities. Moreover, aggressive tumors with “cold” and immunosuppressive microenvironments may not be effectively suppressed solely through innate immunotherapy. Herein, we propose a multifaceted immunostimulating nanoparticle (Mn-MC NP), which integrates manganese II (Mn 2+ ) coordinated photosensitizers (chlorin e6, Ce6) and STING agonists (MSA-2) within a PEGylated nanostructure. In Mn-MC NPs, Ce6 exerts potent phototherapeutic effects, facilitating tumor ablation and inducing immunogenic cell death to elicit robust adaptive antitumor immunity. MSA-2 activates the STING pathway powered by Mn 2+ , thereby promoting innate antitumor immunity. The Mn-MC NPs feature a high drug-loading capacity (63.42 %) and directly ablate tumor tissue while synergistically boosting both adaptive and innate immune responses. In subsutaneous tumor mouse models, the Mn-MC NPs exhibit remarkable efficacy in not only eradicating primary tumors but also impeding the progression of distal and metastatic tumors through synergistic immunotherapy. Additionally, they contribute to preventing tumor recurrence by fostering long-term immunological memory. Our multifaceted immunostimulating nanoparticle holds significant potential for overcoming limitations associated with insufficient antitumor immunity and ineffective cancer treatment.
研究领域:
纳米技术
·
癌症免疫疗法
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药学
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免疫学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Xiuli Zhang,Mingjing Wei,Zhigang Zhang,Yarong Zeng,Feihong Zou,Sibo Zhang,Zhiping Wang,Fentian Chen,Hualong Xiong,Yufang Li,Lizhi Zhou,Tingting Li,Qingbing Zheng,Hai Yu,Jun Zhang,Ying Gu,Qinjian Zhao,Shaowei Li,Ningshao Xia
The cGAS-STING pathway and the Mevalonate Pathway are druggable targets for vaccine adjuvant discovery. Manganese (Mn) and bisphosphonates are known to exert adjuvant effects by targeting these two pathways, respectively. This study found the synergistic potential of the two pathways in enhancing immune response. Risedronate (Ris) significantly amplified the Mn adjuvant early antibody response by 166-fold and fortified its cellular immunity. However, direct combination of Mn 2+ and Ris resulted in increased adjuvant toxicity (40% mouse mortality). By the combination of doping property of hydroxyapatite (HA) and its high affinity for Ris, we designed Ris-functionalized Mn-HA micro-nanoparticles as an organic-inorganic hybrid adjuvant, named MnHARis. MnHARis alleviated adjuvant toxicity (100% vs. 60% survival rate) and exhibited good long-term stability. When formulated with the varicella-zoster virus glycoprotein E (gE) antigen, MnHARis triggered a 274.3-fold increase in IgG titers and a 61.3-fold surge in neutralization titers while maintaining a better long-term humoral immunity compared to the aluminum adjuvant. Its efficacy spanned other antigens, including ovalbumin, HPV18 VLP, and SARS-CoV-2 spike protein. Notably, the cellular immunity elicited by the group of gE + MnHARis was comparable to the renowned Shingrix®. Moreover, intratumoral co-administration with an anti-trophoblast cell surface antigen 2 nanobody revealed synergistic antitumor capabilities. These findings underscore the potential of MnHARis as a potent adjuvant for augmenting vaccine immune responses and improving cancer immunotherapy outcomes.
研究领域:
免疫学
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药学
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纳米技术
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病毒学
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癌症研究
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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
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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）