丝素蛋白增强的肽自组装水凝胶的制备及其在肿瘤类器官构建中的应用

doi:10.6040/j.issn.1671-9352.0.2025.167

《山东大学学报(理学版)》 ›› 2025, Vol. 60 ›› Issue (10): 117-126.doi: 10.6040/j.issn.1671-9352.0.2025.167

• • 上一篇

丝素蛋白增强的肽自组装水凝胶的制备及其在肿瘤类器官构建中的应用

刘欣怡¹,李洁龄¹,王安河¹,李琦¹,白硕^1,2*

1.中国科学院过程工程研究所生物药制备与递送全国重点实验室, 北京 100190;2.中国科学院大学化学工程学院, 北京 100049

发布日期:2025-10-17
通讯作者: 白硕(1981— ),男,研究员,博士,研究方向为凝胶生物材料. E-mail:baishuo@ipe.ac.cn
作者简介:刘欣怡(1999— ),女,硕士研究生,研究方向为凝胶生物材料. E-mail:13720613057@163.com*通信作者:白硕(1981— ),男,研究员,博士,研究方向为凝胶生物材料. E-mail:baishuo@ipe.ac.cn
基金资助:
国家自然科学基金资助项目(22277121,22072155,22307117,22407126);中国科学院先导项目(XDB0520300);国家重点研发计划项目(2023YFC3904601);生物药制备与递送全国重点实验室开放基金项目(2023KF-06);生物药制备与递送全国重点实验室部署项目(2024-FX-B-06)

Preparation of silk fibroin enhanced peptide self-assembled hydrogel and its application in the construction of tumor organoids

LIU Xinyi¹, LI Jieling¹, WANG Anhe¹, LI Qi¹, BAI Shuo^1,2*

1. State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China;
2. School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China

Published:2025-10-17

摘要/Abstract

摘要： 癌症是威胁人类健康的重大疾病,传统肿瘤研究模型如细胞系、动物模型等存在显著局限性,开发新型研究模型成为迫切需求。肿瘤类器官技术可精准模拟肿瘤特征,但依赖成分复杂的Matrigel基质胶,模型稳定性和可重复性差。肽自组装水凝胶因生物相容性好、组分明确、可模拟天然胞外基质微结构等优势,成为Matrigel理想的替代材料。但其机械性能和生物稳定性较弱,难以满足类器官长期培养的需求。本工作创新性地将丝素蛋白引入肽自组装水凝胶体系以优化其性能,从而满足类器官培养对基质性能的要求:丝素蛋白掺杂可增强短肽分子间相互作用,提升水凝胶力学强度和生物稳定性,且不破坏其仿生的纳米纤维微结构。以该水凝胶培养胶质瘤类器官,一周内即可形成百微米级的类器官,并且类器官内细胞存活率高达90%。本研究为解决传统肿瘤类器官培养的基质材料问题提供了新方案,有望提升肿瘤类器官培养质量和稳定性,为肿瘤研究和精准医疗提供更可靠模型。

关键词: 肽自组装, 丝素蛋白, 复合水凝胶, 肿瘤类器官, 力学性能

Abstract: Cancer is a major disease threatening human health. Traditional tumor research models such as cell lines and animal models have significant limitations, making the development of new research models an urgent need. Tumor organoid technology can accurately simulate tumor characteristics, but it relies on Matrigel with complex components, resulting in poor stability and reproducibility of the model. Peptide self-assembled hydrogels have become ideal alternatives to Matrigel due to their advantages such as good biocompatibility, clear components, and the ability to mimic the microstructures of natural extracellular matrices. However, their mechanical properties and biological stability are weak, making it difficult to meet the long-term culture requirements of organoids. This work innovatively introduced silk fibroin into the peptide self-assembled hydrogel system to optimize its performance and meet the matrix property requirements for organoid culture. Silk fibroin doping could enhance the interactions between short peptide molecules, improve the mechanical strength and biological stability of the hydrogel, and did not damage its biomimetic nanofibrous microstructure. Using this hydrogel to culture glioma organoids could form hundred-micron-level organoids within one week, and the cell viability within the organoids was as high as 90%. This study provided a new solution to the matrix material problem in traditional tumor organoid culture, was expected to improve the quality and stability of tumor organoid culture, and provided a more reliable model for tumor research and precision medicine.

Key words: peptide self-assembly, silk fibroin, composite hydrogel, tumor organoid, mechanical properties

中图分类号:

O648

刘欣怡,李洁龄,王安河,李琦,白硕. 丝素蛋白增强的肽自组装水凝胶的制备及其在肿瘤类器官构建中的应用[J]. 《山东大学学报(理学版)》, 2025, 60(10): 117-126.

LIU Xinyi, LI Jieling, WANG Anhe, LI Qi, BAI Shuo. Preparation of silk fibroin enhanced peptide self-assembled hydrogel and its application in the construction of tumor organoids[J]. JOURNAL OF SHANDONG UNIVERSITY(NATURAL SCIENCE), 2025, 60(10): 117-126.

参考文献

[1] MACDONALD W J, PURCELL C, PINHO-SCHWERMANN M, et al. Heterogeneity in cancer[J]. Cancers, 2025, 17(3):441.
[2] YAMAGUCHI M. Extracellular regucalcin: a potent suppressor in the cancer cell microenvironment[J]. Cancers, 2025, 17(2):240.
[3] GROZINSKY-GLASBERG S, SHIMON I, RUBINFELD H. The role of cell lines in the study of neuroendocrine tumors[J]. Neuroendocrinology, 2012, 96(3):173-187.
[4] VINCENT K M, POSTOVIT L M. Investigating the utility of human melanoma cell lines as tumour models[J]. Oncotarget, 2017, 8(6):10498-10509.
[5] TOYOHARA J, ISHIWATA K. Animal tumor models for PET in drug development[J]. Annals of Nuclear Medicine, 2011, 25(10):717-731.
[6] BABU V, PAUL N, YU R. Animal models and cell lines of pancreatic neuroendocrine tumors[J]. Pancreas, 2013, 42(6):912-923.
[7] LI Z T, ZHENG W B, WANG H J, et al. Application of animal models in cancer research: recent progress and future prospects[J]. Cancer Management and Research, 2021, 13:2455-2475.
[8] PU F F, GUO H Y, SHI D Y, et al. The generation and use of animal models of osteosarcoma in cancer research[J]. Genes & Diseases, 2024, 11(2):664-674.
[9] YANG L, YANG S, LI X Y, et al. Tumor organoids: from inception to future in cancer research[J]. Cancer Letters, 2019, 454:120-133.
[10] LV J J, DU X, WANG M M, et al. Construction of tumor organoids and their application to cancer research and therapy[J]. Theranostics, 2024, 14(3):1101-1125.
[11] MAO Y N, HU H L. Establishment of advanced tumor organoids with emerging innovative technologies[J]. Cancer Letters, 2024, 598:217122.
[12] RASSOMAKHINA N V, RYAZANOVA A Y, LIKHOV A R, et al. Tumor organoids: the era of personalized medicine[J]. Biochemistry(Moscow), 2024, 89(1):S127-S147.
[13] BIAN S, REPIC M, GUO Z M, et al. Genetically engineered cerebral organoids model brain tumor formation[J]. Nature Methods, 2018, 15(8):631-639.
[14] DOMINIJANNI A, DEVARASETTY M, SOKER S. Manipulating the tumor microenvironment in tumor organoids induces phenotypic changes and chemoresistance[J]. iScience, 2020, 23(12):101851.
[15] BROGUIERE N, ISENMANN L, HIRT C, et al. Growth of epithelial organoids in a defined hydrogel[J]. Advanced Materials, 2018, 30(43):1801621.
[16] SHI W, MIRZA S, KUSS M, et al. Embedded bioprinting of breast tumor cells and organoids using low-concentration collagen-based bioinks[J]. Advanced Healthcare Materials, 2023, 12(26):2300905.
[17] XU Z Y, HUANG J J, LIU Y, et al. Extracellular matrix bioink boosts stemness and facilitates transplantation of intestinal organoids as a biosafe Matrigel alternative[J]. Bioengineering & Translational Medicine, 2023, 8(1):e10327.
[18] YAN X H, ZHU P L, LI J B. Self-assembly and application of diphenylalanine-based nanostructures[J]. Chemical Society Reviews, 2010, 39(6):1877-1890.
[19] ALTUNBAS A, POCHAN D J. Peptide-based and polypeptide-based hydrogels for drug delivery and tissue engineering[J]. Topics in Current Chemistry, 2012, 310:135-167.
[20] LI J L, XING R R, BAI S, et al. Recent advances of self-assembling peptide-based hydrogels for biomedical applications[J]. Soft Matter, 2019, 15(8):1704-1715.
[21] XU H Y, FENG J, DAI N, et al. Self-assembling peptide hydrogel scaffold integrating stem cell-derived exosomes for infected bone defects[J]. Journal of Biomaterials Science, Polymer Edition, 2024, 35(10):1511-1522.
[22] YANG P X, YAO X M, TIAN X, et al. Supramolecular peptide hydrogel epitope vaccine functionalized with CAR-T cells for the treatment of solid tumors[J]. Materials Today Bio, 2025, 31:101517.
[23] DING L Q, LIU X Y, SUN R Y, et al. Silk fibroin-enhanced peptide self-assembled biomimetic hydrogel for 3D cell proliferation[J]. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2025, 720:137123.
[24] LI J L, XUE Y, WANG A H, et al. Polyaniline functionalized peptide self-assembled conductive hydrogel for 3D cell culture[J]. Gels, 2022, 8(6):372.
[25] JIAN H L, LI X, DONG Q Q, et al. In vitro construction of liver organoids with biomimetic lobule structure by a multicellular 3D bioprinting strategy[J]. Cell Proliferation, 2023, 56(5):e13465.
[26] LI X, JIAN H L, HAN Q Q, et al. Three-dimensional(3D)bioprinting of medium toughened dipeptide hydrogel scaffolds with Hofmeister effect[J]. Journal of Colloid and Interface Science, 2023, 639:1-6.
[27] SHUAI Y J, ZHENG M D, KUNDU S C, et al. Bioengineered silk protein-based 3D in vitro models for tissue engineering and drug development: from silk matrix properties to biomedical applications[J]. Advanced Healthcare Materials, 2024, 13(28):2401458.
[28] SHEN C Y, ZHOU Z Y, LI R Y, et al. Silk fibroin-based hydrogels for cartilage organoids in osteoarthritis treatment[J]. Theranostics, 2025, 15(2):560-584.
[29] YAO X, ZOU S Z, FAN S N et al. Bioinspired silk fibroin materials: from silk building blocks extraction and reconstruction to advanced biomedical applications[J]. Materials Today Bio, 2022, 16:100381
[30] ZOU S Z, YAO X, SHAO H L, et al. Nonmulberry silk fibroin-based biomaterials: impact on cell behavior regulation and tissue regeneration[J]. Acta Biomaterialia, 2022, 153:68-84.
[31] WANG L L, CHEN Z J, YAN Y F, et al. Fabrication of injectable hydrogels from silk fibroin and angiogenic peptides for vascular growth and tissue regeneration[J]. Chemical Engineering Journal, 2021, 418:129308.
[32] KIM S H, YEON Y K, LEE J M, et al. Precisely printable and biocompatible silk fibroin bioink for digital light processing 3D printing[J]. Nature Communications, 2018, 9:1620.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed

丝素蛋白增强的肽自组装水凝胶的制备及其在肿瘤类器官构建中的应用

Preparation of silk fibroin enhanced peptide self-assembled hydrogel and its application in the construction of tumor organoids

PDF (PC)

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 2

多维度评价

本文评价

推荐阅读 0

[1]	袁清献,高丽兰,李瑞欣,刘迎节,林祥龙,张西正. 3D打印丝素蛋白-Ⅱ型胶原软骨支架[J]. 山东大学学报（理学版）, 2018, 53(3): 82-87.
[2]	秦晓怡,高丽兰,张慧,张春秋,葛洪玉,刘志动. 不同压缩速率下关节软骨力学性能的有限元模拟[J]. 山东大学学报（理学版）, 2016, 51(3): 34-39.