CoChat
Sign Up
Cited by 13

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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
Open this paper in CoChat — free account

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…

Overview

Integrity signals

Registry

Crossref · 10.1016/j.jconrel.2025.113835

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Show all 1 references

Research works printed but not linked: 39

  1. Rubahamya, 2024, Clinical translation of antibody drug conjugate dosing in solid tumors from preclinical mouse data, Sci. Adv., 10, eadk1894, 10.1126/sciadv.adk1894 · DOI
  2. Nguyen, 2024, The mechanisms of nanoparticle delivery to solid tumours, Nature Reviews Bioengineering, 2, 201, 10.1038/s44222-024-00154-9 · DOI
  3. Amruta, 2023, Vasculature organotropism in drug delivery, Adv. Drug Deliv. Rev., 201, 10.1016/j.addr.2023.115054 · DOI
  4. Yang, 2020, Enhancement of tumour penetration by nanomedicines through strategies based on transport processes and barriers, J. Control. Release, 328, 28, 10.1016/j.jconrel.2020.08.024 · DOI
  5. Cabral, 2024, Controlling the biodistribution and clearance of nanomedicines, Nature Reviews Bioengineering, 2, 214, 10.1038/s44222-023-00138-1 · DOI · Paper page
  6. Shen, 2024, Enhancing drug penetration in solid tumors via nanomedicine: evaluation models, strategies and perspectives, Bioact Mater, 32, 445
  7. Mitchell, 2021, Engineering precision nanoparticles for drug delivery, Nat. Rev. Drug Discov., 20, 101, 10.1038/s41573-020-0090-8 · DOI · Paper page
  8. Ma, 2018, Modular assembly of proteins on nanoparticles, Nat. Commun., 9, 1489, 10.1038/s41467-018-03931-4 · DOI
  9. Teesalu, 2009, C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration, Proc. Natl. Acad. Sci. U. S. A., 106, 16157, 10.1073/pnas.0908201106 · DOI · Paper page
  10. Balistreri, 2021, A widespread viral entry mechanism: the C-end rule motif-neuropilin receptor interaction, Proc. Natl. Acad. Sci. U. S. A., 118, 10.1073/pnas.2112457118 · DOI
  11. Ruoslahti, 2017, Tumor penetrating peptides for improved drug delivery, Adv. Drug Deliv. Rev., 110-111, 3, 10.1016/j.addr.2016.03.008 · DOI
  12. Pan, 2024, Glycoengineering-based anti-PD-1-iRGD peptide conjugate boosts antitumor efficacy through T cell engagement, Cell Rep Med, 5
  13. Christian, 2003, Nucleolin expressed at the cell surface is a marker of endothelial cells in angiogenic blood vessels, J. Cell Biol., 163, 871, 10.1083/jcb.200304132 · DOI
  14. Romano, 2019, Nucleolin-based targeting strategies for cancer therapy: from targeted drug delivery to cytotoxic ligands, Drug Discov. Today, 24, 1985, 10.1016/j.drudis.2019.06.018 · DOI
  15. Thongchot, 2023, Nucleolin-based targeting strategies in cancer treatment: focus on cancer immunotherapy (review), Int. J. Mol. Med., 52, 10.3892/ijmm.2023.5284 · DOI
  16. Shin, 2018, Aberrant expression of CITED2 promotes prostate cancer metastasis by activating the nucleolin-AKT pathway, Nat. Commun., 9, 4113, 10.1038/s41467-018-06606-2 · DOI
  17. Liu, 2022, A pro-metastatic tRNA fragment drives Nucleolin oligomerization and stabilization of its bound metabolic mRNAs, Mol. Cell, 82, 2604, 10.1016/j.molcel.2022.05.008 · DOI
  18. Chen, 2024, Precise preparation of supramolecular spherical nucleic acids for Nucleolin-targeted gene delivery, Angew. Chem. Int. Ed. Engl., 63, 10.1002/anie.202410744 · DOI
  19. Liu, 2023, A non-G-Quadruplex DNA aptamer targeting NCL for diagnosis and therapy in bladder Cancer, Adv. Healthc. Mater., 12, 10.1002/adhm.202370117 · DOI
  20. Li, 2017, A water-soluble nucleolin aptamer-paclitaxel conjugate for tumor-specific targeting in ovarian cancer, Nat. Commun., 8, 1390, 10.1038/s41467-017-01565-6 · DOI
  21. Henke, 2008, Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo, Nat. Biotechnol., 26, 91, 10.1038/nbt1366 · DOI
  22. Thapa, 2020, TRAIL therapy and prospective developments for cancer treatment, J. Control. Release, 326, 335, 10.1016/j.jconrel.2020.07.013 · DOI
  23. Dhillon, 2024, Aponermin: first approval, Drugs, 84, 459, 10.1007/s40265-024-02004-9 · DOI
  24. Deng, 2020, TRAIL of Hope meeting resistance in Cancer, trends, Cancer, 6, 989
  25. Yang, 2023, Molecular superglue-mediated higher-order assembly of TRAIL variants with superior apoptosis induction and antitumor activity, Biomaterials, 295, 10.1016/j.biomaterials.2023.121994 · DOI
  26. Sharma, 2022, Recent updates on innovative approaches to overcome drug resistance for better outcomes in cancer, J. Control. Release, 346, 43, 10.1016/j.jconrel.2022.04.007 · DOI · Paper page
  27. Li, 2024, Tumor-penetrating iRGD facilitates penetration of poly(floxuridine-ketal)-based nanomedicine for enhanced pancreatic cancer therapy, J. Control. Release, 369, 444, 10.1016/j.jconrel.2024.04.004 · DOI
  28. Ruoslahti, 2016, Tumor penetrating peptides for improved drug delivery, Adv. Drug Deliv. Rev., 110-111, 3, 10.1016/j.addr.2016.03.008 · DOI
  29. Tong, 2022, Progress in cancer drug delivery based on AS1411 oriented nanomaterials, J Nanobiotechnology, 20, 57, 10.1186/s12951-022-01240-z · DOI
  30. Hwang, 2010, A nucleolin-targeted multimodal nanoparticle imaging probe for tracking cancer cells using an aptamer, J. Nucl. Med., 51, 98, 10.2967/jnumed.109.069880 · DOI
  31. Song, 2022, Advances in aptamer-based nuclear imaging, Eur. J. Nucl. Med. Mol. Imaging, 49, 2544, 10.1007/s00259-022-05782-0 · DOI
  32. Okesola, 2018, Multicomponent self-assembly as a tool to harness new properties from peptides and proteins in material design, Chem. Soc. Rev., 47, 3721, 10.1039/C8CS00121A · DOI
  33. Keri, 2024, Next generation of multispecific antibody engineering, Antib Ther, 7, 37
  34. Lin, 2024, Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment, Cell, 187, 10.1016/j.cell.2024.10.016 · DOI
  35. Tao, 2017, Targeted delivery to tumor-associated Pericytes via an Affibody with high affinity for PDGFRbeta enhances the in vivo antitumor effects of human TRAIL, Theranostics, 7, 2261, 10.7150/thno.19091 · DOI
  36. Montinaro, 2023, Harnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries, Cell Death Differ., 30, 237, 10.1038/s41418-022-01059-z · DOI
  37. von Karstedt, 2017, Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy, Nat. Rev. Cancer, 17, 352, 10.1038/nrc.2017.28 · DOI · Paper page
  38. Spencer, 2009, Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis, Nature, 459, 428, 10.1038/nature08012 · DOI
  39. Pillai, 2024, De novo design of allosterically switchable protein assemblies, Nature, 632, 911, 10.1038/s41586-024-07813-2 · DOI

Cited by

Sorted by citations

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)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review