ADVANCED MATERIALS
·
2024
·
IF 27.4
Qingshuang Zou,Ke Liao,Guangchao Li,Xin Huang,Yongwei Zheng,Gun Yang,Min Luo,Evelyn Y. Xue,Chuanqing Lan,Shuai Wang,Yao Shen,Dixian Luo,Dennis K. P. Ng,Quan Liu
The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. The first single-element nanomaterial based on chromium nanoparticles (Cr NPs) for cancer photo-metallo-immunotherapy has been reported previously. Herein, an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy, is reported. The results show that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib can promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that can “warm” the “cold” tumor microenvironment (TME). The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor can significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr 3+ ions, which are the major degradation product of these nanocomposites, can increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures (TLSs) in the tumor tissues, facilitating the CAR-T cell infiltration.
研究领域:
肿瘤学
·
免疫疗法
·
纳米技术
·
生物医学工程
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 18
·9199
·
IF 4.9
Jia Fu,Yanan Zhang,Yifan Lv,Ruilin Li,Hongchen Gu,Jingxing Yang
Genetic engineering of macrophages, particularly for chimeric antigen receptor macrophage (CAR-M) therapy, holds great promise for immunotherapy, yet is constrained by the challenge of efficient gene delivery into primary macrophages, which are notoriously resistant to transfection. While conventional strategies focus on optimizing the physicochemical properties of lipid nanoparticles (LNP), they often fail to overcome the intrinsic biological barriers of these cells. Here, we introduced a “bioactive nanocarrier” paradigm, hypothesizing that incorporating a cellular modulator directly into LNP structure can synergistically overcome these barriers. We designed and synthesized a novel LNP by integrating the pro-inflammatory fatty acid, arachidonic acid (ARA), as a functional structural component (ARA-LNP). Systematic optimization of the ARA content and mRNA payload revealed a formulation that achieves high transfection efficiency (83.76%) in primary M2-polarized bone marrow-derived macrophages (BMDMs), a cell type that recapitulates pro-tumoral phenotype in the tumor microenvironment. Leveraging this advanced delivery platform, we successfully generated HER2-targeting CAR-M that demonstrated potent and specific phagocytic activity against HER2-expressing tumor cells in vitro. This work presents a powerful strategy where the nanocarrier itself transiently modulates the target cell state to enhance gene delivery, providing a new design principle for engineering macrophages and other hard-to-transfect immune cells for therapeutic applications.
研究领域:
免疫学
·
肿瘤学
·
纳米医学
·
基因治疗
·
转化医学
·
分子药剂学
·
细胞工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2023
·
IF 8.2
Yuxiang Tang,WeiQi Yao,Hang Hu,Wei Xiong,Heng Mei,Yu Hu
TGF-β is widely existed in tumor microenvironment, taking part in tumorigenesis process including angiogenesis, cancer associated fibroblast (CAF) proliferation, and immunosuppression. It inhibited the activation, proliferation, migration and differentiation of T cells, in which way caused a limited therapeutic effects of chimeric antigen receptor T (CAR-T) towards solid tumor such as lymphoma. To targeted block TGF-β at tumor site, we take advantages of nano-techniques to deliver TGF-β inhibitors LY2157299 (LY) towards the tumor sites, in order to help achieve a improved and long-term functions of CAR-T towards lymphoma. Based on amphipathic hydroxyethyl starch-polycaprolactone (HES-PCL), LY and photosensitizer indocyanine green (ICG) were co-loaded in HES-PCL to achieve LY/ [email protected] nanoparticle. The enhanced function of CAR-T benefited from LY/ [email protected] were verified through lymphoma Raji cells in vitro and Nod scid gamma mice engrafted with the Raji cells in vivo. LY was targeted transported to tumor site and accelerated release by mild ICG photothermal. Chemokines CXCL9/10/11 at the tumor site relevant to CAR-T migration and chemokines receptor CXCR3 of CAR-T could be up-regulated by LY, thus facilitated the enhanced accumulation of CAR-T at lymphoma site. T effector memory cells differentiation could also be accelerated by LY/ [email protected] Combined therapy of LY/ [email protected] and CAR-T achieved 2.4 times higher antitumor activity and 2.7 times higher relapse inhibiting rates than CAR-T alone within 15 days and 11 days, respectively. The results suggested that LY/ [email protected] facilitated the enhanced therapeutic index of CAR-T cells towards lymphoma simply and safely, it may be further potentiated applied for other solid tumors.
研究领域:
肿瘤学
·
免疫治疗
·
纳米技术
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2024
·Vol. 43
·期 1
·1-16
·
IF 11.4
Li Xing,Sun Shiyu,Zhang Wansong,Liang Ziwei,Fang Yitong,Sun Tianhu,Wan Yong,Ma Xingcong,Zhang Shuqun,Xu Yang,Tian Ruilin
Background Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Current treatment options are limited and often ineffective. CAR T cell therapy has shown success in treating hematologic malignancies, and there is growing interest in its potential application in solid tumors, including GBM. However, current CAR T therapy lacks clinical efficacy against GBM due to tumor-related resistance mechanisms and CAR T cell deficiencies. Therefore, there is a need to improve CAR T cell therapy efficacy in GBM. Methods We conducted large-scale CRISPR interference (CRISPRi) screens in GBM cell line U87 MG cells co-cultured with B7-H3 targeting CAR T cells to identify genetic modifiers that can enhance CAR T cell-mediated tumor killing. Flow cytometry-based tumor killing assay and CAR T cell activation assay were performed to validate screening hits. Bioinformatic analyses on bulk and single-cell RNA sequencing data and the TCGA database were employed to elucidate the mechanism underlying enhanced CAR T efficacy upon knocking down the selected screening hits in U87 MG cells. Results We established B7-H3 as a targetable antigen for CAR T therapy in GBM. Through large-scale CRISPRi screening, we discovered genetic modifiers in GBM cells, including ARPC4 , PI4KA , ATP6V1A , UBA1 , and NDUFV1 , that regulated the efficacy of CAR T cell-mediated tumor killing. Furthermore, we discovered that TNFSF15 was upregulated in both ARPC4 and NDUFV1 knockdown GBM cells and revealed an immunostimulatory role of TNFSF15 in modulating tumor-CAR T interaction to enhance CAR T cell efficacy. Conclusions Our study highlights the power of CRISPR-based genetic screening in investigating tumor-CAR T interaction and identifies potential druggable targets in tumor cells that confer resistance to CAR T cell killing. Furthermore, we devised targeted strategies that synergize with CAR T therapy against GBM. These findings shed light on the development of novel combinatorial strategies for effective immunotherapy of GBM and other solid tumors.
CAS / MDL:
研究领域:
肿瘤学
·
免疫学
·
基因组学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Biomedical Engineering
·
2023
·Vol. 7
·期 9
·1129-1141
·
IF 28.1
Li Xianlei,Gong Ningqiang,Tian Falin,Zhang Shangkun,Zhang Yuxuan,Wang Yufei,Qing Guangchao,Wang Yongchao,Li Fangzhou,Xu Yihui,Zhang Linlin,Wang Jinjin,Ni Qiankun,Gan Yaling,Gu Chaojiang,Jiang Huaidong,Huang Xingxu,Shi Xinghua,Zhang Tongcun,Wu Yan,Liang Xing-Jie
The infusion of chimaeric antigen receptor (CAR) T cells can trigger the release of life-threatening supraphysiological levels of pro-inflammatory cytokines. However, uncertainty regarding the timing and severity of such cytokine release syndrome (CRS) demands careful monitoring of the conditions required for the administration of neutralizing antibodies. Here we show that a temperature-sensitive hydrogel conjugated with antibodies for the pro-inflammatory cytokine interleukin-6 (IL-6) and subcutaneously injected before the infusion of CAR-T cells substantially reduces the levels of IL-6 during CRS while maintaining the therapy’s antitumour efficacy. In immunodeficient mice and in mice with transplanted human haematopoietic stem cells, the subcutaneous IL-6-adsorbing hydrogel largely suppressed CAR-T-cell-induced CRS, substantially improving the animals’ survival and alleviating their levels of fever, hypotension and weight loss relative to the administration of free IL-6 antibodies. The implanted hydrogel, which can be easily removed with a syringe following a cooling-induced gel–sol transition, may allow for a shift in the management of CRS, from monitoring to prevention.
研究领域:
肿瘤学
·
免疫治疗
·
生物医学工程
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2022
·
IF 5.738
Da-Lai Xu,Yuan-Qing He,Bin Xiao,Yuan Si,Jian Shi,Xue-Ang Liu,Lei Tian,Qian Ren,Ya-Song Wu,Yi Zhu
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy with a limited response to current therapies. Novel and effective treatment is urgently needed. Herein, a chimeric antigen receptor (CAR)-NK92 cell line, with an interleukin (IL)-15Rα-sushi/IL-15 complex and a Programmed cell death-1(PD1) signal inverter was constructed and named SP (
S
ushi-IL15-
P
D1). We showed that CAR expression enabled SP cells to proliferate independently of IL-2 and became more resistant to nutrition starvation-induced apoptosis. Meanwhile, SP cells were more effective than NK92 in PDAC cell killing assays in vitro and in vivo, and there was a positive correlation between the killing capability of SP cells and PD-L1 expression in pancreatic cancer cells. Based on the synergistic and comprehensive effects of the special CAR structure, the adhesion, responsiveness, degranulation efficiency, targeted delivery of cytotoxic granule content, and cytotoxicity of SP cells were significantly stronger than those of NK92. In conclusion, the SP cell line is a promising adoptive immunotherapy cell line and has potential value as an adjuvant treatment for pancreatic cancer, especially in patients with high PD-L1 expression.Keywords: pancreatic ductal adenocarcinoma, Chimeric antigen receptor (CAR), IL-15, IL-15Rα-sushi, programmed cell death ligand 1 (PD-L1), adoptive immunotherapy
研究领域:
肿瘤学
·
免疫疗法
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Chunwei Tang,Weiqiang Jing,Kun Han,Zhenmei Yang,Shengchang Zhang,Miaoyan Liu,Jing Zhang,Xiaotian Zhao,Ying Liu,Chongdeng Shi,Qihao Chai,Ziyang Li,Maosen Han,Yan Wang,Zhipeng Fu,Zuolin Zheng,Kun Zhao,Peng Sun,Danqing Zhu,Chen Chen,Daizhou Zhang,Dawei Li,Shilei Ni,Tao Li,Jiwei Cui,Xinyi Jiang
Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR) mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion target) siRNA to MΦs in situ, yielding CAR-MΦs with boosted bactericidal potency. Specifically, our results demonstrated that the engineered MΦs could efficiently phagocytose and digest MRSA intracellularly, preventing immune evasion by the “superbug” MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform for multidrug-resistant (MDR) bacterial infections and should be confirmed in clinical trials.
研究领域:
传染病学
·
纳米技术
·
免疫学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Polymer Materials
·
2026
·
IF 5.2
Dong Yiwei,Wang Chenxu,Ren Bing,Mu Yongchang,Liu Yunlan,Li Jie,Han Jing
Gelatin-based
gels are attractive for flexible sensing because
of their reshapeability and potential sustainability. However, their
practical use is still limited by weak mechanical robustness and an
insufficient strain sensitivity. Here, a highly sensitive and reshaped
gelatin-based eutectogel was developed by combining urchin-like conductive
particles with a DES exchange strategy. Sodium caseinate (SC)-MWCNT@liquid
metal (LM) particles were introduced as multiscale conductive units.
The deep eutectic solvent (DES) exchange process reconstructed the
gel network by promoting polymer chain entanglement and facilitating
gelatin triple-helix formation. As a result, the optimized GSML eutectogel
achieved a tensile strength of 3.71 MPa, an elongation at break of
381.66%, and a gauge factor (GF) of 7.6 ( R 2 = 0.98). It maintained stable sensing signals over 1000 stretching
cycles at a 100% strain. Moreover, the GSML could be rapidly reshaped
through simple thermal reprocessing. The retention of triple-helix
structures during reshaping allowed the eutectogel to maintain good
mechanical strength. As a proof of concept, the GSML sensor was integrated
into a single-handed control glove for unmanned car control, achieving
an average recognition accuracy of 94.75%. This work provides a strategy
for designing highly sensitive and reshaped gelatin-based eutectogels
for human–machine interaction applications.
✓ 已验证
产品关联
DOI
高影响因子
Nature Communications
·
2026
·Vol. 17
·期 1
·1663
·
IF 18.1
Zhang Yan,Liu Zhiqiang,Kong Wenyu,Ao Yanxiao,Zhang Rui,Du Yanan
CAR-macrophage (CAR-M) therapy holds promise for the treatment of tumor and fibrotic diseases, yet genetic engineering remains the main efficacy-enhancing approach. Here we develop a non-genetic strategy using viscoelastic hydrogel to mechanically prime CAR-Ms. CAR-Ms exhibit potent phagocytosis of activated fibroblasts and collagen-degradation capacity, and hydrogel priming further enhances their cytotoxicity. Mechanistically, viscoelastic hydrogel priming reduces CAR-M membrane tension, which triggers membrane CAR to disassemble from clusters into dispersed monomers and dimers, leading to enhanced downstream signaling. In pulmonary fibrosis models, hydrogel-primed CAR-Ms demonstrate superior therapeutic outcomes, showing fibrosis reduction and microenvironment improvement. This study highlights CAR-M therapy’s potential for pulmonary fibrosis treatment and offers a distinct approach to improve CAR-M efficacy by physical stimuli.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·Vol. 10
·期 26
·2301872
·
IF 15.1
Yuanzheng Long,Cheng Yang,Yulong Wu,Bohan Deng,Ziwei Li,Naveed Hussain,Kuangyu Wang,Ruyue Wang,Xian He,Peng Du,Zeliang Guo,Jialiang Lang,Kai Huang,Hui Wu
The increasing demand for clean energy conversion and storage has increased interest in hydrogen production via electrolytic water splitting. However, the simultaneous production of hydrogen and oxygen in this process poses a challenge in extracting pure hydrogen without using ionic conducting membranes. Researchers have developed various innovative designs to overcome this issue, but continuous water splitting in separated tanks remains a desirable approach. This study presents a novel, continuous roll-to-roll process that enables fully decoupled hydrogen evaluation reaction (HER) and oxygen evolution reaction (OER) in two separate electrolyte tanks. The system utilizes specially designed “cable-car” electrodes (CCE) that cycle between the HER and OER tanks, resulting in continuous hydrogen production with a purity of over 99.9% and Coulombic efficiency of 98% for prolonged periods. This membrane-free water splitting system offers promising prospects for scaled-up industrial-scale green hydrogen production, as it reduces the cost and complexity of the system, and allows for the use of renewable energy sources to power the electrolysis process, thus reducing the carbon footprint of hydrogen production.
研究领域:
能源科学
·
材料科学
·
环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL
·
2024
·
IF 45.5
Tongtong Zhang,Shengjun Tan,Na Tang,Yuanqing Li,Chenze Zhang,Jing Sun,Yanyan Guo,Hui Gao,Yujia Cai,Wen Sun,Chenxin Wang,Liangzheng Fu,Huijing Ma,Yachao Wu,Xiaoxuan Hu,Xuechun Zhang,Peter Gee,Weihua Yan,Yahui Zhao,Qiang Chen,Baocheng Guo,Haoyi Wang,Yong E. Zhang
Experimental studies on DNA transposable elements (TEs) have been limited in scale, leading to a lack of understanding of the factors influencing transposition activity, evolutionary dynamics, and application potential as genome engineering tools. We predicted 130 active DNA TEs from 102 metazoan genomes and evaluated their activity in human cells. We identified 40 active (integration-competent) TEs, surpassing the cumulative number (20) of TEs found previously. With this unified comparative data, we found that the Tc1/ mariner superfamily exhibits elevated activity, potentially explaining their pervasive horizontal transfers. Further functional characterization of TEs revealed additional divergence in features such as insertion bias. Remarkably, in CAR-T therapy for hematological and solid tumors, Mariner2_AG (MAG), the most active DNA TE identified, largely outperformed two widely used vectors, the lentiviral vector and the TE-based vector SB100X. Overall, this study highlights the varied transposition features and evolutionary dynamics of DNA TEs and increases the TE toolbox diversity.
研究领域:
分子生物学
·
遗传学
·
基因组学
·
医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL
·
2026
·
IF 45.1
Feng Li,Yuxing Hu,Yan Wang,Xiao Zhang,Shaowei Qiu,Xiaoming Hu,Wenjing Wang,Shuang Wang,Peilin Guo,Cui Song,Huaiji Wang,Changhao He,Jie Sun,Di Yu,Shuhua Yi,Jun Wei,Feifan Liu,Caopei Zheng,Jianxiang Wang,Yuhua Li,Guanghui Ma,Wei Wei
Although promising, chimeric antigen receptor T (CAR T) cell therapy for treating leukemias still faces the critical challenge of antigen modulation, which causes resistance. Building from our clinical insight that both diverse types of leukemia cells and corresponding CAR T cells strongly express CD71 (a ferritin receptor), we designed a ferritin aggregation cell engager (FACE) that can anchor to the CAR T cell surface, guide CAR T cells to face leukemia cells, and facilitate CAR recognition of cognate antigens. In vitro and in vivo experiments with diverse leukemia patient-derived cells and leukemia patient-derived xenograft models show that our FACE-CAR T cells succeed in enhancing therapeutic efficacy with good biosafety, lowering the antigen threshold for overcoming antigen modulation, and even loading chemodrugs in ferritin for combination therapy. This avidity engineering provides a neotype, facile, universal, and flexible approach for improving the efficacy of CAR T cell therapy for diverse refractory leukemias.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）