韩雪祥--中国科学院分子细胞科学卓越创新中心

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人才队伍

韩雪祥
研究员，研究组长，博士生导师
E-mail: xuexiang.han@sibcb.ac.cn
实验室主页: www.sibcb.ac.cn/hanlab

个人简介：

2010-2014年，上海大学，工学学士
2014-2019年，清华大学（国家纳米科学中心联合培养），理学博士（导师赵宇亮院士、李亚栋院士）
2020-2024年，宾夕法尼亚大学，博士后（合作导师Michael J. Mitchell教授）
2024年2月起任中国科学院分子细胞科学卓越创新中心（生物化学与细胞生物学研究所）研究员，研究组长，博士生导师

社会任职：

研究方向：

纳米药物与RNA递送

研究工作：

　　继小分子药物和抗体药物之后，RNA药物正在掀起第三代药物浪潮，应用领域由新冠病毒向其他传染病、癌症、罕见病以及细胞治疗和基因编辑适应症方向拓展。目前，已批准上市十余种小核酸药物和mRNA药物。RNA分子量大、亲水性强、负电荷高，难以穿过表面同为负电荷的细胞膜，并且RNA结构极不稳定，易被降解，所以需要递送载体才能实现RNA药物的胞内转染。脂质纳米粒（Lipid Nanoparticle，LNP）是目前主流的非病毒递送载体，其主要包含可电离脂质、磷脂、胆固醇和聚乙二醇化脂质四个组分。
本课题组以新型脂质分子合成为基础，通过大型脂质文库构建、高通量筛选、配方优化和活体测试并结合多种生物学手段，解析LNP“结构与递送效率”、“结构与靶向性”和“结构与生物学效应”的关系，为满足不同需求的RNA药物递送提供保障。同时，课题组开发新型RNA药物，探究其在疫苗、蛋白替代、基因沉默、基因编辑、细胞治疗等方向的生物医学应用，为临床转化提供理论和技术支持。

承担科研项目情况：

代表论著：

1. X. Han⁺, M.G. Alameh⁺, N. Gong⁺, L. Xue⁺, Y. Xu, D. Weissman*, M.J. Mitchell*. Fast and facile synthesis of amidine-incorporated degradable lipids for versatile mRNA delivery in vivo. Nat. Chem., 2024, DOI: 10.1038/s41557-024-01557-2.
2. X. Han⁺, J. Xu⁺, Y. Xu, M.G. Alameh, L. Xue, N. Gong, J.M. Wilson, D. Weissman, M.J. Mitchell*. In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors. Nat. Commun., 2024, 15: 1762.
3. X. Han⁺, M.G. Alameh⁺, K. Butowska, J.J. Knox, K. Lundgreen, M. Ghattas, N. Gong, L. Xue, Y. Xu, M. Lavertu, P. Bates, J. Xu, G. Nie, Y. Zhong, D. Weissman*, M.J. Mitchell*. Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines. Nat. Nanotechnol., 2023, 18: 1105.
4. N. Gong⁺, X. Han⁺, L. Xue⁺, R. El-Mayta, A.E. Metzloff, M.M. Billingsley, A.G. Hamilton, M.J. Mitchell*. In situ PEGylation of CAR T cells alleviates cytokine release syndrome and neurotoxicity. Nat. Mater., 2023, 22: 1571.
5. X. Han⁺, N. Gong⁺, L. Xue, M.M. Billingsley, R. El-Mayta, S.J. Shepherd, M.G. Alameh, D. Weissman, M.J. Mitchell*. Ligand-Tethered Lipid Nanoparticles for Targeted RNA Delivery to Treat Liver Fibrosis. Nat. Commun.,2023, 14: 75.
6. X. Huang⁺, E. Kon⁺, X. Han⁺, X. Zhang, N. Kong, M.J. Mitchell*, P. Dan*, W. Tao*. Nanotechnology-based strategies against SARS-CoV-2 variants, Nat. Nanotechnol., 2022，17: 1027-1037.
7. K. Butowska⁺, X. Han⁺, N. Gong, R. El-Mayta, R.M. Haley, L. Xue, W. Zhong, W. Guo, K. Wang, M.J. Mitchell*. Doxorubicin-conjugated siRNA lipid nanoparticles for combination cancer therapy. Acta Pharm. Sin. B, 2023, 13: 1429-1437.
8. H. Zhang⁺, X. Han⁺, M.G. Alameh, S.J. Shepherd, M.S. Padilla, L. Xue, K. Butowska, D. Weissman, M.J. Mitchell*. Rational design of anti-inflammatory lipid nanoparticles for mRNA delivery. J. Biomed. Mater. Res. A, 2022, 110: 1101-1108. (selected as the cover)
9. X. Han⁺, H. Zhang⁺, K. Butowska, K.L. Swingle, M.G. Alameh, D. Weissman, M.J. Mitchell*. An Ionizable Lipid Toolbox for RNA Delivery, Nat. Commun., 2021, 12, 7233. (Top 25 most read Nat. Commun. articles in 2021)
10. Y. Zhang⁺, X. Han⁺, G. Nie*, Responsive and activable nanomedicines for remodeling the tumor microenvironment, Nat. Protoc., 2021, 16 (1): 405-430.
11. X. Han, M.J. Mitchell*, G. Nie*. Nanomaterials for Therapeutic RNA Delivery, Matter, 2020, 3(6): 1948-1975.
12. X. Han⁺, K. Cheng⁺, Y. Xu⁺, Y. Wang, H. Min, Y. Zhang, X. Zhao, R. Zhao, G.J. Anderson, L. Ren, G. Nie*, Y. Li*, Modularly Designed Peptide Nanoprodrug Augments Anti-Tumor Immunity of PD-L1 Checkpoint Blockade by Targeting Indoleamine 2, 3-Dioxygenase, J. Am. Chem. Soc., 2020, 142: 2490-2496.
13. X. Han⁺, Y. Xu⁺, M. Geranpayehvaghei, G.J. Anderson, Y. Li*, G. Nie*, Emerging nanomedicines for anti-stromal therapy against desmoplastic tumors, Biomaterials, 2020, 232: 119745.
14. X. Han⁺, Y. Xu⁺, Y. Li*, X. Zhao, Y. Zhang, H. Min, G.J. Anderson, Y. Zhao*, G. Nie*, An extendable star-like nanoplatform for functional and anatomical imaging-guided photothermal oncotherapy, ACS Nano, 2019, 13(4): 4379-4391.
15. X. Han, G. Nie*,Say no to tumors: NO matters, Matter, 2019, 1(4): 794-796.
16. Y. Xu⁺, X. Han⁺, Y. Li*, H. Min, X. Zhao, Y. Zhang, Y. Qi, J. Shi, S. Qi, Y. Bao*, G. Nie*, Sulforaphane mediates glutathione depletion via polymeric nanoparticles to restore cisplatin chemosensitivity, ACS Nano, 2019, 13(11): 13445-13455.
17. X. Han, Y. Li*, Y. Xu, X. Zhao, Y. Zhang, X. Yang, Y. Wang, R. Zhao, G.J. Anderson, Y. Zhao*, G. Nie*, Reversal of pancreatic desmoplasiaby re-educating stellate cells with a tumour microenvironment-activated nanosystem, Nat. Commun., 2018, 9: 3390.
18. R. Zhao⁺, X. Han⁺, Y. Li*, H. Wang, T. Ji, Y. Zhao, G. Nie*, Photothermal effect enhanced cascade-targeting strategy for improved pancreatic cancer therapy by gold nanoshell@mesoporous silica nanorod, ACS Nano, 2017, 11(8): 8103-8113.
19. N. Gong, X. Han, L. Xue, M.M. Billingsley, X. Huang, R. El-Mayta, J. Qin, N.C. Sheppard, C.H. June, M.J. Mitchell. Small-molecule-mediated control of the anti-tumour activity and off-tumour toxicity of a supramolecular bispecific T cell engager. Nat. Biomed. Eng., 2024, 8:513-528.
20. A.G. Hamilton, K.L. Swingle, A.S. Thatte, A.J. Mukalel, H.C. Safford, X. Han, A.E. Metzloff, M.J. Mitchell. High-Throughput In Vivo Screening Identifies Differential Influences on mRNA Lipid Nanoparticle Immune Cell Delivery by Administration Route. ACS Nano, 2024, DOI: 10.1021/acsnano.4c01171.
21. A.E. Metzloff, M.S. Padilla, N. Gong, M.M. Billingsley, X. Han, M. Merolle, D. Mai, C.H. June, M.J. Mitchell. Antigen Presenting Cell Mimetic Lipid Nanoparticles for Rapid mRNA CAR T Cell Cancer Immunotherapy. Adv. Mater., 2024, 2313226.
22. L. Xue, A.G. Hamilton, G. Zhao, Z. Xiao, R. El-Mayta, X. Han, N. Gong, X. Xiong, D. Weissman, M.J. Mitchell. High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models. Nat. Commun., 2024, 15: 1884.
23. A.J. Mukalel, A.G. Hamilton, M.M. Billingsley, J. Li, A.S. Thatte, X. Han, D. Weissman, M.J. Mitchell*. Oxidized mRNA Lipid Nanoparticles for In Situ Chimeric Antigen Receptor Monocyte Engineering. Adv. Funct. Mater., 2024, 2312038.
24. G. Zhao, L. Xue, A.I. Weiner, N. Gong, S. Adams-Tzivelekidis, J. Wong, X. Han, M.J. Mitchell*, A.E. Vaughan*. TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue. Sci. Transl. Med., 2024, 16: eadg6229.
25. L. Xue, A.S. Thatte, D. Mai, R.M. Haley, N. Gong, X. Han, K. Wang, N.C. Sheppard, C.H. June, M.J. Mitchell*. Responsive biomaterials: optimizing control of cancer immunotherapy.Nat. Rev. Mater, 2024, 9: 100.
26. M.M. Billingsley, N. Gong, A.J. Mukalel, A.S. Thatte, R.E. Mayta, S.K. Patel, X. Han, D. Weissman, M.J. Mitchell*. In Vivo mRNA CAR T Cell Engineering via Targeted Ionizable Lipid Nanoparticles with Extrahepatic Tropism. Small, 2023: 2304378.
27. W. Zhong, Y. Lu, X. Han, J. Yang, Z. Qin, W. Zhang, Z. Yu, B. Wu, S. Liu, W. Xu, C. Zheng, X. Xu, W. Guo*. Upregulation of exosome secretion from tumor-associated macrophages plays a key role in the suppression of anti-tumor immunity. Cell Reports, 2023, 42: 113224.
28. S.J. Shepherd, X. Han, A.J. Mukalel, R.E. Mayta, A.S. Thatte, J. Wu, M.S. Padilla, M.G. Alameh, N. Srikumar, D. Lee, D. Weissman, D. Issadore*, M.J. Mitchell*, Throughput-scalable manufacturing of SARS-CoV-2 mRNA lipid nanoparticle vaccines, PNAS, 2023, 120 (33), e2303567120.
29. J. Xu, N. Yan, C. Wang, C. Gao, X. Han, C. Yang, J. Xu, K. Wang, M.J. Mitchell, Y. Zhang*, G. Nie*. Platelet-Mimicking Nanosponges for Functional Reversal of Antiplatelet Agents, Circulation Research, 2023
30. R.E. Mayta, M. Padilla, M. Billingsley, X. Han, M.J. Mitchell*. Testing the In Vitro and In Vivo Efficiency of mRNA-Lipid Nanoparticles Formulated by Microfluidic Mixing. J. Vis. Exp. 2023, 191: e64810.
31. L. Xue, N. Gong, S.J. Shepherd, X. Xiong, X. Liao, X. Han, G. Zhao, D. Weissman, M.J. Mitchell*. Rational Design of Bisphosphonate Lipid-like Materials for mRNA Delivery to the Bone Microenvironment. J. Am. Chem. Soc., 2022,, 144, 22, 9926-9937.
32. S.K. Patel, M.M. Billingsley, C. Frazee, X. Han, K.L. Swingle, J. Qin, M.G. Alameh, K. Wang, D. Weissman, M.J. Mitchell*. Hydroxycholesterol substitution in ionizable lipid nanoparticles for mRNA delivery to T cells. J. Control. Release., 2022, 347: 521-532.
33. H. Parhiz, J.S. Brenner, P. Patel, T.E. Papp, H. Shahnawaz, Q. Li, R. Shi, M. Zamora, A. Yadegari, O.A. Marcos-Contreras, A. Natesan, N. Pardi, V.V. Shuvaev, R. Kiseleva, J. Myerson, T. Uhler, R.S. Riley, X. Han, M.J. Mitchell, K. Lam, J. Heyes, D. Weissman, V. Muzykantov*. Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE). J. Control. Release., 2022, 344: 50-61.
34. K. Cheng, R. Zhao, Y. Li, Y. Qi, Y. Wang, Y. Zhang, H. Qin, Y. Qin, L. Chen, C. Li, J. Liang, Y. Li, J. Xu, X. Han, G.J. Anderson, J. Shi, L. Ren, X. Zhao*, G. Nie*. Bioengineered bacteria-derived outer membrane vesicles as a versatile antigen display platform for tumor vaccination via Plug-and-Display technology. Nat. Commun., 2021, 12(1), 1-16.
35. H. Qin, R. Zhao*, Y. Qin, J. Zhu, L. Chen, C. Di, X. Han, K. Cheng, Y. Zhang, Y. Zhao, J. Shi, G.J. Anderson, Y. Zhao, G. Nie*. Development of a Cancer Vaccine Using In Vivo Click-Chemistry-Mediated Active Lymph Node Accumulation for Improved Immunotherapy. Adv. Mater., 2021, 33(20): 2006007.
36. Y. Li, X. Zhao, X. Liu, K. Cheng, X. Han, Y. Zhang, H. Min, G. Liu, J. Xu, J. Shi, H. Qin, H. Fan, L. Ren, G. Nie. A Bioinspired Nanoprobe with Multilevel Responsive T1-Weighted MR Signal-Amplification Illuminates Ultrasmall Metastases. Adv. Mater., 2020, 32(4): 1906799.
37. H. Min, Y. Qi, Y. Zhang, X. Han, K. Cheng, Y. Liu, H. Liu, J. Hu, G. Nie*, Y. Li*, A Graphdiyne oxide-based iron sponge with photothermally enhanced tumor-specific Fenton chemistry, Adv. Mater., 2020, 32(31): 2000038.
38. X. Zhao, L Li, Y Zhao, H. An, Q. Cai, J. Lang, X. Han, B. Peng, Y. Fei, H. Liu, H. Qin, G. Nie, H. Wang*. In Situ Self-Assembled Nanofibers Precisely Target Cancer-Associated Fibroblasts for Improved Tumor Imaging. Angew. Chem., Int. Ed., 2019, 131: 15431.
39. H. Min, J. Wang, Y. Qin, Y. Zhang,X. Han, Y. Xu, J. Xu, Y. Li, L. Chen, K. Cheng, G. Liu, Y. Li, G. Nie*. Biomimetic metal-organic framework nanoparticles for cooperative combination of antiangiogenesis and photodynamic therapy for enhanced efficacy. Adv. Mater., 2019: 1808200.
40. J. Lang, X. Zhao, X. Wang, Y. Zhao, Y. Li, R. Zhao, K. Cheng, Y. Li, X. Han, X. Zheng, H. Qin, M. Geranpayehvaghei, J. Shi, G.J. Anderson, J. Hao, H. Ren, G. Nie*. Targeted co-delivery of the iron chelator deferoxamine and a HIF1α inhibitor impairs pancreatic tumor growth. ACS Nano, 2019, 13(2): 2176-2189.
41. J. Lang, X. Zhao, Y. Qi, Y. Zhang, X. Han, Y. Ding, J. Guan, T. Ji, Y. Zhao, G. Nie. Reshaping Prostate Tumor Microenvironment To Suppress Metastasis via Cancer-Associated Fibroblast Inactivation with Peptide-Assembly-Based Nanosystem. ACS Nano, 2019, 13:12357.
42. L. Zhang, Y. Qi, H. Min, C. Ni, F. Wang, B. Wang, H. Qin, Y. Zhang, G. Liu, Y. Qin, X. Duan, F. Li, X. Han, N. Tao, L. Zhang, Z. Qin, Y. Zhao, G. Nie*. Cooperatively responsive peptide nanotherapeutic that regulates angiopoietin receptor Tie2 activity in tumor microenvironment to prevent breast tumor relapse after chemotherapy. ACS Nano, 2019, 13(8): 5091-5102.
43. H. Min, Y. Qi, Y. Chen, Y. Zhang, X. Han, Y. Xu, Y. Liu, J. Hu, H. Liu, Y. Li*, G. Nie*. Synthesis and imaging of biocompatible graphdiyne quantum dots. ACS Appl. Mater. Interfaces, 2019, 11: 32798.
44. M. Taleb, Y. Ding, B. Wang, N. Yang, X. Han, C. Du, Y. Qi, Y. Zhang, Z.F. Sabet, H.R. Alanagh, A. Mujeeb, K. Khajeh, G. Nie*. Dopamine Delivery via pH-Sensitive Nanoparticles for Tumor Blood Vessel Normalization and an Improved Effect of Cancer Chemotherapeutic Drugs. Adv. Health. Mater., 2019, 8(18): 1900283.
45. C. Du, Y. Qi, Y. Zhang, Y. Wang, X. Zhao, H. Min, X. Han, J. Lang, H. Qin, Q. Shi, Z. Zhang, X. Tian, G.J. Anderson, Y. Zhao, G. Nie*, Y. Yang*. Epidermal growth factor receptor-targeting peptide nanoparticles simultaneously deliver gemcitabine and olaparib to treat pancreatic cancer with breast cancer 2 (BRCA2) mutation. ACS Nano, 2018, 12(11): 10785-10796
46. F. Li, Y. Li, X. Yang, X. Han, Y. Jiao, T. Wei, D. Yang, H. Xu, G*. Nie*, Highly fluorescent chiral N-S-doped carbon dots from cysteine: affecting cellular energy metabolism, Angew. Chem., Int. Ed., 2018, 130(9): 2401-2406.
47. L. You, J. Wang, T. Liu, Y. Zhang, X. Han, T. Wang, S. Guo, T. Dong, J. Xu, G.J. Anderson, Q. Liu, Y.Z. Chang, X. Lou, G. Nie*, Targeted brain delivery of rabies virus glycoprotein 29-modified deferoxamine-loaded nanoparticles reverses functional deficits in parkinsonian mice, ACS Nano, 2018, 12(5): 4123-4139.
48. X. Zhao, X. Wang, W. Sun, K. Cheng, H. Qin, X. Han, Y. Lin, Y. Wang, J. Lang, R. Zhao, X. Zheng, Y. Zhao, J. Hao, Q.R. Miao, G. Nie, H. Ren*. Precision design of nanomedicines to restore gemcitabine chemosensitivity for personalized pancreatic ductal adenocarcinoma treatment. Biomaterials, 2018, 158: 44.
49. B. Wang, Y. Ding, X. Zhao, X. Han, N. Yang, Y. Zhang, Y. Zhao, X. Zhao, M. Taleb, Q.R. Miao, G. Nie*. Delivery of small interfering RNA against Nogo-B receptor via tumor-acidity responsive nanoparticles for tumor vessel normalization and metastasis suppression. Biomaterials, 2018, 175: 110.
50. Y. Qi, H. Min, A. Mujeeb, Y. Zhang, X. Han, X. Zhao, G.J. Anderson, Y. Zhao, G. Nie*. Injectable hexapeptide hydrogel for localized chemotherapy prevents breast cancer recurrence. ACS Appl. Mater. Interfaces, 2018, 10: 6972.
51. Y. Zhang, J. Wei, S. Liu, J. Wang, X. Han, H. Qin, J. Lang, K. Cheng, Y. Li, Y. Qi, G.J. Anderson, S. Sukumar, S. Li, G. Nie*. Inhibition of platelet function using liposomal nanoparticles blocks tumor metastasis. Theranostics, 2017, 7:1062.
52. F. Li, T. Li, X. Han, H. Zhuang, G. Nie, H. Xu*. Nanomedicine assembled by coordinated selenium-platinum complexes can selectively induce cytotoxicity in cancer cells by targeting the glutathione antioxidant defense system. ACS Biomater. Sci. Eng., 2018, 4: 1954.
53. X. Zhao, X. Wang, L. Fang, C. Lan, X. Zheng, Y. Wang, Y. Zhang, X. Han, S. Li, K. Cheng, Y. Zhao, J. Shi, J. Guo, J. Hao, H. Ren, G. Nie*. A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS-mutant pancreatic cancer. Cancer letters, 2017, 402:61.

获奖及荣誉：

研究组成员：

2024.05.18团建合影