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Natural long-chain saturated fatty acids doped LNPs enabling spleen selective mRNA translation and potent cancer immunotherapy

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Nano Research 2024年第3期17卷 1804-1817页

作者： Fazhan Wang Meng Zhang Meiling Tian Jia Lou longze pan Xiaoke Gao Lijing Zhang Xiaohan Lou Linyu Zhu Yuqiao Sheng Ming Wang Rui Xue Wenjing Deng Shuai Shao Zhihai Qin Medical Research Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Translational Medical Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Department of Neuro-Intensive Care Unit The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Academy of Medical Sciences Zhengzhou UniversityZhengzhou 450052China

Rationally tailored lipid nanoparticles(LNPs)with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines.Selective expression of antigenic protein in lymphoid tissues/organs could improve the immunostimulatory efficacy and safety of LNPs-based mRNA vaccines.Inspired by the metabolic behavior that long-chain saturated fatty acids tending to enter lymphoid tissue rather than the liver,we developed fatty acid-doped LNPs capable of mediating differential protein expressions in the liver and spleen when administered intravenously.When the molar ratio of saturated fatty acid located 60%–70%,the doped LNPs achieved the spleen selective mRNA translation.The mechanism could be attributed to the different cellular uptake behaviors of saturated fatty acids in hepatocytes.Immunization with a model antigen(ovalbumin)mRNA-loaded spleen selective LNPs,we observed enhanced antigen-specific T cell immune responses,and potent immunotherapeutic and immunoprophylactic efficacy in the mouse lymphoma model.Our natural long-chain saturated fatty acids metabolic characteristics-inspired design of LNPs for spleen-selective mRNA vaccines delivery will provide references for designing mRNA vaccines with high efficacy and safety for tumor immunotherapy.

关键词： mRNA vaccine lipid nanoparticles spleen long-chain saturated fatty acid cancer immunotherapy

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Inhibiting collagen Ⅰ production and tumor cell colonization in the lung via miR-29a-3p loading of exosome-/liposome-based nanovesicles

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Acta Pharmaceutica Sinica B 2022年第2期12卷 939-951页

作者： Yan Yan Cancan Du Xixi Duan Xiaohan Yao Jiajia Wan Ziming Jiang Zhongyu Qin Wenqing Li longze pan Zhuoyu Gu Fazhan Wang Ming Wang Zhihai Qin Medical Research Center the First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Academy of Medical Sciences Zhengzhou UniversityZhengzhou 450052China Department of Urology the First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Changzhi Medical College Changzhi 046000China Institute of Biophysics Chinese Academy of SciencesBeijing 100101China

The lung is one of the most common sites for cancer metastasis.Collagens in the lung provide a permissive microenvironment that supports the colonization and outgrowth of disseminated tumor cells.Therefore,down-regulating the production of collagens may contribute to the inhibition of lung metastasis.It has been suggested that mi R-29 exhibits effective anti-fibrotic activity by negatively regulating the expression of collagens.Indeed,our clinical lung tumor data shows that mi R-29 a-3 p expression negatively correlates with collagen I expression in lung tumors and positively correlates with patients’outcomes.However,suitable carriers need to be selected to deliver this therapeutic mi RNA to the lungs.In this study,we found that the chemotherapy drug cisplatin facilitated mi R-29 a-3 p accumulation in the exosomes of lung tumor cells,and this type of exosomes exhibited a specific lung-targeting effect and promising collagen down-regulation.To scale up the preparation and simplify the delivery system,we designed a lung-targeting liposomal nanovesicle(by adjusting the molar ratio of DOTAP/cholesterol-mi RNAs to 4:1)to carry mi R-29 a-3 p and mimic the exosomes.This liposomal nanovesicle delivery system significantly down-regulated collagen I secretion by lung fibroblasts in vivo,thus alleviating the establishment of a pro-metastatic environment for circulating lung tumor cells.

关键词： Lung metastasis miR-29a-3p CollagenⅠ Liposomal nanovesicle Exosomes Fibroblasts Pre-metastatic niche

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Stability Comparison Between Grid-forming and Grid-following Based Wind Farms Integrated MMC-HVDC

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Journal of Modern Power Systems and Clean Energy 2023年第4期11卷 1341-1355页

作者： Rongcai pan Dong Liu Shan Liu Jie Yang longze Kou Guangfu Tang China Electric Power Research Institute Beijing 100192Chinaand he is also with the State Key Laboratory of Advanced Power Transmission Technology and Beijing Key Laboratory of DC Grid Technology&SimulationBeijing 102209China State Key Laboratory of Advanced Power Transmission Technology and Beijing Key Laboratory of DC Grid Technology&Simulation Beijing 102209China

Grid-forming(GFM)control based high-voltage DC(HVDC)systems and renewable energy sources(RESs)provide support for enhancing the stability of power systems.However,the interaction and coordination of frequency support between the GFM-based modular multilevel converter based HVDC(MMC-HVDC)and grid-following(GFL)based RESs or GFM-based RESs have not been fully investigated,which are examined in this study.First,the detailed AC-and DC-side impedances of GFM-based MMC-HVDC are analyzed.The impedance characteristics of GFL-and GFM-based wind turbines are next analyzed.Then,the influences of GFL-and GFM-based wind farms(WFs)on the DC-and AC-side stabilities of WF-integrated MMC-HVDC systems are compared and evaluated.The results show that the GFM-based wind turbine performs better than the GFL-based wind turbine.Accordingly,to support a receiving-end AC system,the corresponding frequency supporting strategies are proposed based on the GFM control for WF-integrated MMC-HVDC systems.The GFM-based WF outperforms the GFL-based WF in terms of stability and response time.Simulations in PSCAD/EMTDC demonstrate the DC-and AC-side stability issues and seamless grid support from the RESs,i.e.,WFs,to the receiving-end AC system.

关键词： Renewable energy source(RES) modular multilevel converter(MMC) wind farm grid-forming(GFM) highvoltage direct current

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转录调控因子ALsR表达强度对枯草芽孢杆菌合成乙偶姻和2,3-丁二醇的影响

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应用与环境生物学报 2020年第4期26卷 753-759页

作者：刘会灵刘栓英潘龙泽张显徐美娟邵明龙杨套伟饶志明江南大学生物工程学院工业生物技术教育部重点实验室无锡214122

转录调控因子ALs R是枯草芽孢杆菌中赖氨酸家族的转录调控因子,负责调控丙酮酸到乙偶姻和2,3-丁二醇合成途径中乙酰乳酸合成酶和乙酰乳酸脱羧酶的表达.为探究枯草芽孢杆菌生产乙偶姻和2,3-丁二醇过程中ALs R的最适表达强度,选取5个不同... 详细信息

转录调控因子ALs R是枯草芽孢杆菌中赖氨酸家族的转录调控因子,负责调控丙酮酸到乙偶姻和2,3-丁二醇合成途径中乙酰乳酸合成酶和乙酰乳酸脱羧酶的表达.为探究枯草芽孢杆菌生产乙偶姻和2,3-丁二醇过程中ALs R的最适表达强度,选取5个不同强度的启动子来调控ALs R的表达,首先以绿色荧光蛋白(GFP)作为报告基因表征了不同强度启动子的转录活性,然后使用这些不同强度的启动子来调控ALs R的表达,研究ALs R的表达强度对枯草芽孢杆菌乙偶姻和2,3-丁二醇发酵的影响.结果发现,在使用表达水平较强的组成型启动子Pals SD调控ALs R表达时,细胞的发酵周期延长8 h,细胞密度有所下降,乙偶姻和2,3-丁二醇产量也有一定程度的下降.当使用较弱的启动子Psrf A、Pbdh A、Pzwf、Pals R调控ALs R表达时,ALS和ALDC酶活分别提高1.15-2.25倍和2.4-4.8倍,此时比较适于乙偶姻和2,3-丁二醇的合成,乙偶姻和2,3-丁二醇的产量分别提高了9.24%-19.63%和7.16%-14.91%,同时副产物乳酸和乙酸的产量分别降低了5.45%-18.18%和19.46%-31.21%,其中在启动子Pbdh A调控ALs R表达时,即ALS和ALDC酶活分别提高1.9倍和4.1倍,此时最适于乙偶姻和2,3-丁二醇的发酵生产,乙偶姻和2,3-丁二醇的产量分别提高了19.6%和14.9%,副产物乳酸和乙酸的产量也显著下降.本研究发现过量地表达转录调控因子ALs R会对细胞的生长造成影响,不利于乙偶姻和2,3-丁二醇的发酵,而适度强化表达转录调控因子ALs R不会对细胞的生长造成影响,可以有效地提高乙偶姻和2,3-丁二醇的产量,降低发酵过程中的副产物乙酸和乳酸的积累.(图5表4参34)

关键词： ALsR 乙偶姻 2 3-丁二醇启动子枯草芽孢杆菌

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玉米秸秆还田养分释放规律及对玉米根际土和根系酶活性的影响

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沈阳师范大学学报（自然科学版） 2018年第6期36卷 539-544页

作者：潘晶齐诗月肖露侯万园汲茏泽沈阳师范大学生命科学学院沈阳110034

秸秆是有机肥料的基本资源,秸秆直接还田或间接还田能提高土壤有机质含量、改善土壤肥力。研究了秸秆覆盖和深埋2种秸秆还田方式下,秸秆腐解,碳、氮、磷释放规律及对玉米根际土和根系酶活性的影响,结果表明:2种秸秆还田方式下,经过150d... 详细信息

秸秆是有机肥料的基本资源,秸秆直接还田或间接还田能提高土壤有机质含量、改善土壤肥力。研究了秸秆覆盖和深埋2种秸秆还田方式下,秸秆腐解,碳、氮、磷释放规律及对玉米根际土和根系酶活性的影响,结果表明:2种秸秆还田方式下,经过150d的腐解,秸秆腐解率分别为:70.6%(深埋,S2)和55.3%(覆盖,B1);有机碳释放率分别为77.6%(S2)和70.3%(B1);氮释放率分别为45.7%(S2)和37.6%(B1);磷释放率分别为65.2%(S2)和63.7%(B1)。相比秸秆覆盖,秸秆深埋更能提高根际土脲酶、蔗糖酶和过氧化氢酶活性。秸秆深埋处理根系活力、超氧化物歧化酶和过氧化氢酶活性高于秸秆覆盖处理;玉米秸秆还田对根系丙二醛含量没有影响。秸秆还田能有效提高土壤的有机质、氮和磷量,改善土壤活性。

关键词：秸秆还田腐解酶活性

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