A biohybrid chiral hydrogel enhances preclinical postoperative glioblastoma therapy by multi-pronged inhibition of tumour stemness

Data availability

The RNA-sequencing data are available in the NCBI Gene database under accession code GSE308216. All data supporting the findings of this study are included within the Article and its Supplementary Information. Additional information is available from the corresponding authors upon reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (22374026 to L.L.), the National University of Singapore (NUHSRO/2020/133/Startup/08, NUHSRO/2023/008/NUSMed/TCE/LOA, NUHSRO/2021/034/TRP/09/Nanomedicine and 23-0173-A0001 to X.C.), the National Medical Research Council (MOH-001388-00, CG21APR1005, MOH-001500-00, MOH-001609-00 and MOH-001740-01 to X.C.), the Singapore Ministry of Education (MOE-000387-00 and MOE-MOET32023-004 to X.C.), the National Research Foundation (NRF-000352-00 to X.C.), the Agency for Science, Technology and Research (A*STAR) (H25J5a0024 to X.C.) and the NUS-Nanjing University Research Collaboration Fund 2025 Award.

Author information

Authors and Affiliations

MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou, China

Tingting Cui, Sixue Chen, Siqin Liu, Jun Wang, Rujiang Ao, Huilan Cai, Hongwei Huang, Meili Yu, Shanshan Peng & Lisen Lin
Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore

Tingting Cui & Xiaoyuan Chen
Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

Tingting Cui & Xiaoyuan Chen
Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China

Xuegang Niu
Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

Xiaoyuan Chen
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

Xiaoyuan Chen
Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

Xiaoyuan Chen
Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore

Xiaoyuan Chen

Authors

Tingting Cui
Sixue Chen
Siqin Liu
Xuegang Niu
Jun Wang
Rujiang Ao
Huilan Cai
Hongwei Huang
Meili Yu
Shanshan Peng
Xiaoyuan Chen
Lisen Lin

Contributions

T.C., X.C. and L.L. conceived and designed the project. T.C., S.L. and J.W. prepared and characterized the platform. T.C. and S.L. performed the in vitro experiments. T.C., S.C., S.L., X.N. and J.W. carried out the in vivo experiments on mice. R.A., H.C., H.H., M.Y. and S.P. participated in the analysis of data. T.C., X.C. and L.L. analysed the results and co-wrote the paper. All authors reviewed the paper and approved the final version.

Corresponding authors

Correspondence to Xiaoyuan Chen or Lisen Lin.

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Competing interests

X.C. is a co-founder of and holds shares in Yantai Lannacheng Biotechnology.

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Nature Nanotechnology thanks Hao Cheng, Paolo Decuzzi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Comparison of the efficacy of D-gel@GSNP and conventional NF-κB inhibitors in reducing GL261 GSC stemness.

a, Immunofluorescence images of CD133, SOX2 and nuclei in treated Hoechst⁻CD133⁺ cells. b, Relative percentages of GL261 GSCs (CD133⁺SOX2⁺) in different groups. c, Images of tumorspheres formed by cells after various treatments. d, H&E-stained images of brain sections from mice implanted with treated cells, harvested on day 18 post-tumor inoculation. e, In vivo bioluminescent images of mice implanted with treated cells on day 18 post-tumor inoculation. f, g, Ratios of tumorsphere numbers (f) and tumorsphere diameters (g) in various groups relative to those in the PBS group. h, Ratios of tumor size to brain size in brain sections from mice undergoing stereotactic injection of treated cells. i, Bioluminescent signal intensity in tumor-bearing mice. Data in a and c-e are representative of three independent experiments with similar results. Data in b and f–i are presented as mean ± SD (n = 3 independent experiments). Statistical significance was assessed using by a one-way ANOVA with Tukey’s multiple comparisons test. In b and f–i, P denotes the statistical significance relative to the PBS group, and ¹P denotes the statistical significance relative to the D-gel@GSNP group. Controls: In a–i, Hoechst⁻CD133⁺ cells with PBS and cytokine cocktail treatments.

Source data

Extended Data Fig. 2 Establishment of CT2A-GBM resection mouse model and in vitro stemness reduction by D-gel@GSNP.

a, Schematic representation of treatment schedule for CT2A-GBM resection mouse model. b, CD133, Nestin and OCT4 immunohistochemical images of brain tissue. c, Micrographs of H&E-stained brain tissues from CT2A-GBM-bearing mice undergoing surgical debulking. d, Bright-field image of the CT2A-GBM organoid and immunostaining for CD31, SOX2, GFAP, CD3, and CD11b, corresponding to vasculature, GSCs, astrocytes, T cells, and myeloid cells, respectively. e, In vitro binding capacity of chiral hydrogels encapsulating GSNP or PLGA core to IL-6, PTN, CXCL12, TGF-β and WNT derived from CT2A-GBM organoids. f, Immunofluorescence images of CD133, OCT4 and nuclei in treated non-SP cells and Hoechst⁻CD133⁺ cells. g, Relative percentages of CT2A GSCs (CD133⁺OCT4⁺) in different groups. Data in b–d and f are representative of three independent experiments with similar results. Data in e and g are presented as mean ± SD (n = 3 biological replicates). Statistical significance in e and g was assessed using a one-way ANOVA with a Tukey’s multiple comparisons test. In e, ¹P denotes the statistical significance of cytokine concentration differences in tissues between each treatment group and the PBS group, and ²P denotes the statistical significance of cytokine concentration differences in gels between each treatment group and the D-gel@NP group. In g, P denotes the statistical significance relative to the PBS group, and ¹P denotes the statistical significance relative to the D-gel@GSNP group. Controls: in e, PBS; in f and g, Hoechst⁻CD133⁺ cells with PBS and cytokine cocktail treatments. Panel a created with BioRender.com.

Source data

Extended Data Fig. 3 Distribution and clearance profiles of GSNP-aPD1 and AuNC during hydrogel degradation in the CT2A-GBM mouse model.

a, Immunofluorescent images of brain tissues showing colocalization of GSNP-aPD1 (red) and microglia (green) at different time points after intracavity injection of D-gel@GSNP-aPD1. b, Immunofluorescent images of brain tissues showing colocalization of GSNP-aPD1 (red) and blood vessels (green) at different time points after intracavity injection of D-gel@GSNP-aPD1. c, Fluorescence images of CLN showing distribution of GSNP-aPD1 (red). d, Immunofluorescent images of brain tissues showing colocalization of AuNC (red) and microglia (green) at different time points after intracavity injection of D-gel@GSNP-aPD1. e, Immunofluorescent images of brain tissues showing colocalization of AuNC (red) and blood vessels (green) at different time points after intracavity injection of D-gel@GSNP-aPD1. f, Fluorescence images of CLN showing distribution of AuNC (red). g, Brain clearance profile of AuNC in CT2A-GBM mouse model after intracavity injection of D-gel@GSNP-aPD1 detected by ICP-MS analysis. h, H&E-stained brain sections at varying distances from the anterior cerebrum on day 18 post-hydrogel injection (day 30 post-tumor inoculation). Data in a–f and h are representative of three independent experiments with similar results. In g, data are presented as mean ± SD (n = 4 biological replicates). GSNP-aPD1: DiI-labeled membrane, red; microglia: FITC-labeled Iba1 (ionized calcium-binding adapter molecule 1), green; blood vessels: FITC-dextran 70, green; AuNC: intrinsic fluorescence, red; cell nuclei stained with DAPI, Blue.

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Cui, T., Chen, S., Liu, S. et al. A biohybrid chiral hydrogel enhances preclinical postoperative glioblastoma therapy by multi-pronged inhibition of tumour stemness. Nat. Nanotechnol. (2025). https://doi.org/10.1038/s41565-025-02064-2

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Received: 28 September 2024
Accepted: 14 October 2025
Published: 26 December 2025
Version of record: 26 December 2025
DOI: https://doi.org/10.1038/s41565-025-02064-2

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Extended data

Extended Data Fig. 1 Comparison of the efficacy of D-gel@GSNP and conventional NF-κB inhibitors in reducing GL261 GSC stemness.

Extended Data Fig. 2 Establishment of CT2A-GBM resection mouse model and in vitro stemness reduction by D-gel@GSNP.

Extended Data Fig. 3 Distribution and clearance profiles of GSNP-aPD1 and AuNC during hydrogel degradation in the CT2A-GBM mouse model.

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