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Cyclic Tat peptide promotes nanomedicine permeation in tumor microenvironments through reducing affinity and maintaining binding ability
  • +14
  • Hanxiao Liu,
  • Zhongjie Tang,
  • Xuehui Duan,
  • Xiaotian Zhao,
  • Jialing He,
  • Yan Du,
  • Zewei Sun,
  • Xinlong Liu,
  • Yinuo Li,
  • Xiaohan Li,
  • Yulei Li,
  • Gang Shen,
  • Teng Liu,
  • Wei Xu,
  • Kun Zhao,
  • Yixuan Tang,
  • Chong Li
Hanxiao Liu
Shandong First Medical University
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Zhongjie Tang
Southwest University
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Xuehui Duan
Shandong First Medical University
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Xiaotian Zhao
Shandong University
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Jialing He
Army Medical University
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Yan Du
Shandong First Medical University
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Zewei Sun
Shandong First Medical University
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Xinlong Liu
Southwest University
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Yinuo Li
Shandong First Medical University
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Xiaohan Li
Shandong First Medical University
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Yulei Li
Shandong First Medical University
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Gang Shen
Sichuan Province Sichuan University of Traditional Chinese Medicine
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Teng Liu
Shandong First Medical University
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Wei Xu
Shandong First Medical University
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Kun Zhao
Shandong University
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Yixuan Tang
Shandong First Medical University

Corresponding Author:[email protected]

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Chong Li
Southwest University
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Abstract

Nanomedicine has emerged as a potent weapon against cancer, yet its therapeutic potential is hampered by limited diffusion within tumor tissues. Cell-penetrating peptides (CPPs), such as the trans-activator of transcription (Tat) peptide, can facilitate interactions between carriers and cells; however, their capacity to penetrate cell layers remains limited. Here, we present evidence that cyclic Tat (cTat) can effectively enhance the penetration of nanoparticles into tumors. Compared with linear Tat, cTat exhibited a 10-fold increase in the dissociation constant (Kd) but a nearly dissociation rate constant (Koff) with the cell membrane. This facilitated easier uptake and penetration of cTat-modified liposomes (cTat-Lip) into tumor cells. In vivo studies corroborated these findings; cTat-Lip demonstrated higher tumor penetration and a more even distribution compared to Tat-Lip. Furthermore, we evaluated the impact of cTat-Lip in mouse tumor models and patient-derived xenograft (PDX) models. We confirmed that after enhancing tumor penetration, DOX-loaded cTat-Lip could modulate the immune microenvironment at the tumor site, increasing the proportion of M1-type macrophages and promoting tumor therapy. These results highlight the substantial impact of two-dimensional structure modification of CPPs like Tat on their targeting affinity, emphasize of reducing the peptide’s targeting affinity to achieve enhanced tumor penetration and improved therapeutic outcomes.