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Multivalent assembly of nucleolin-targeted F3 peptide potentiates TRAIL's tumor penetration and antitumor effects

Tao, Ze, Li, Yingying, Huang, Yunchuan, Hu, Liqiang, Wang, Shisheng, Wan, Lin, She, Tianshan, Shi, Qiuxiao, Lu, Sifen, Wang, Xinyue, Zhong, Yi, Su, Tao, Wang, Xinyuan, Long, Dan, Li, Yan, Zhang, Jie, Wang, Lijun, Long, Tingting, Zhu, Hong, Lu, Xiaofeng, Yang, Hao·2025·Journal of Controlled Release
DOI 10.1016/j.jconrel.2025.113835
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Abstract

Tumor-targeting drug delivery holds great promise for cancer treatment but faces significant challenges in penetrating solid tumors to achieve optimal therapeutic efficacy. By harnessing the natural tissue-penetration effect conferred by the CendR motif, we identified that the nucleolin (NCL)-targeted peptide F3 possesses tumor-penetrating capabilities. Co-administration of F3 with doxorubicin and the apoptosis-inducing protein TRAIL enhanced effective tumor penetration and improved antitumor activity. Taking advantage of TRAIL's natural self-trimerization, we developed a novel fusion protein, F3-TRAIL. This design enabled the trivalent assembly of F3 when fused with TRAIL, significantly enhancing its binding to NCL-positive tumor endothelial and parenchymal cells, resulting in deeper tumor penetration and superior antitumor effects compared to TRAIL alone. Mechanistic studies revealed that the multivalent F3-enhanced engagement with tumor cells potentiated TRAIL to trigger death receptor-dependent apoptosis signaling, even in TRAIL-resistant tumor cells. Building on this success, we constructed F3-HexaTR using the SpyCatcher/SpyTag superglue ligation system to generate a hexameric TRAIL, further amplifying cytotoxicity and antitumor efficacy. Combined analysis of data from TCGA and GTEx revealed significantly elevated NCL expression across 18 solid tumor types, underscoring the clinical potential of F3-directed targeted therapy. These findings highlight that F3-mediated NCL…

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Metadata

Authors
Tao, Z., Li, Y., Huang, Y., Hu, L., Wang, S., Wan, L., She, T., Shi, Q., Lu, S., Wang, X., Zhong, Y., Su, T., Wang, X., Long, D., Li, Y., Zhang, J., Wang, L., Long, T., Zhu, H., Lu, X., & Yang, H.
Venue
Journal of Controlled Release
Publisher
Elsevier BV
Published
2025-07
Volume
383
Pages
113835
ISSN
0168-3659
DOI
10.1016/j.jconrel.2025.113835
Cited by
13
References
1
Language
en
Licence
Funders
  • Natural Science Foundation of Sichuan Province (2025ZNSFSC0785)
  • National Natural Science Foundation of China (81102366, 82172731, 82173727, 82402718, 82204684)

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CoChat. (2026). Citation check: Multivalent assembly of nucleolin-targeted F3 peptide potentiates TRAIL's tumor penetration and antitumor effects. https://app.cochat.ai/papers/10.1016/j.jconrel.2025.113835
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Tao, Z., Li, Y., Huang, Y., Hu, L., Wang, S., Wan, L., She, T., Shi, Q., Lu, S., Wang, X., Zhong, Y., Su, T., Wang, X., Long, D., Li, Y., Zhang, J., Wang, L., Long, T., Zhu, H., . . . Yang, H. (2025). Multivalent assembly of nucleolin-targeted F3 peptide potentiates TRAIL's tumor penetration and antitumor effects. Journal of Controlled Release. https://doi.org/10.1016/j.jconrel.2025.113835