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

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

  • J Control Release. 2025 Jul 10:383:113835. doi: 10.1016/j.jconrel.2025.113835.
Ze Tao 1,  Yingying Li 2,  Yunchuan Huang 3,  Liqiang Hu 4,  Shisheng Wang 1,  Lin Wan 5,  Tianshan She 3,  Qiuxiao Shi 6,  Sifen Lu 7,  Xinyue Wang 3,  Yi Zhong 6,  Tao Su 6,  Xinyuan Wang 6,  Dan Long 1,  Yan Li 8,  Jie Zhang 9,  Lijun Wang 10,  Tingting Long 11,  Hong Zhu 12,  Xiaofeng Lu 13,  Hao Yang 14
Affiliations

Affiliations

  • 1 Division of Liver surgery and NHC Key Lab of Transplant Engineering and Immunology, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Department of Laboratory Medicine, the West China Second University Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Division of Liver surgery and NHC Key Lab of Transplant Engineering and Immunology, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 West China-California Research Center for Predictive Intervention Medicine, Chengdu 610041, China.
  • 5 Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 6 Proteomics-Metabolomics Platform, Core facilities, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 7 Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 8 Lung Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 9 SCMPA Key Laboratory for Quality Research and Control of Chemical Medicine, Chengdu Institute for Drug Control, Chengdu 610041, China.
  • 10 Department of Ophthalmology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu 610031, China.
  • 11 Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 12 Division of Abdominal Tumor Multimodality Treatment Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 13 Division of Liver surgery and NHC Key Lab of Transplant Engineering and Immunology, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: xiaofenglu@scu.edu.cn.
  • 14 Division of Liver surgery and NHC Key Lab of Transplant Engineering and Immunology, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu 610041, China; Proteomics-Metabolomics Platform, Core facilities, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yanghao@scu.edu.cn.
PMID: 40355045 DOI: 10.1016/j.jconrel.2025.113835
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 targeting is an effective strategy to overcome tumor penetration barriers, particularly for protein drug delivery. This multivalent assembly approach represents an innovative avenue for enhancing the therapeutic efficacy of various agents in the treatment of solid tumors.

Keywords

Drug delivery; F3 peptide; Nucleolin; TRAIL; Tumor penetration; Tumor-targeting therapy.

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