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Background <p>Melanoma, the most aggressive skin cancer, remains challenging to treat due to limited therapeutic options. Sonodynamic therapy (SDT) has emerged as a promising strategy for combating malignant tumors. However, the excessive accumulation of lactate in the tumor microenvironment after SDT limits the activation of immune cells, leading to the unsatisfactory therapeutic effect of SDT. Fat mass and obesity-associated (FTO) inhibition can effectively inhibit glycolysis of melanoma cells and relieve the obstacle of immune cell activation caused by lactate. FTO inhibiting in tumors eliminates metabolic barriers to T cell activation and further enhances the antitumor effect of CD8 + T cells. Combining FTO inhibition with SDT may enhance tumor cell elimination and remodel the immunosuppressive tumor immune microenvironment.</p> Methods <p>We prepared nanoparticles through filming-rehydration method and the electrostatic adsorption method. The inhibition effects of nanoparticles on FTO and glycolysis were verified by detecting protein expression and lactate production. The therapeutic effect of nanoparticles on melanoma was evaluated by detecting the cytotoxicity of tumor cells and the infiltration of immune cells.</p> Results <p>In this study, tLyp-1 modified ultrasound phase-transforming nanoparticles loaded with sonosensitizer (Ce6) and FTO siRNA were constructed to achieve FTO inhibition and SDT. The tLyp-1 peptide modification facilitated efficient tumor targeting function and enhanced deep tissue penetration, therefore improving drug delivery efficacy. Ce6 produced reactive oxygen species (ROS) in response to ultrasound to induce immunogenic cell death (ICD) in tumor cells. At the same time, ultrasound promoted FTO siRNA transfection to inhibit B16-F10 cells glycolysis, which significantly increased the activation and infiltration of dendritic cells (DCs) and T lymphocytes in the tumor microenvironment, effectively enhanced the therapeutic effect of SDT and inhibited tumor growth.</p> Conclusion <p>This study demonstrated that si-Ce6@tLyP-1 NPs serve as a platform for targeted the tumor site and efficiently deliver siFTO and Ce6. The realization of FTO inhibition combined with SDT provides an effective treatment strategy for the treatment of melanoma.</p> Graphical Abstract <p></p>

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Peptide-modified phase-transition nanoparticles co-deliver FTO siRNA and Ce6 for sonodynamic metabolism-immunotherapy of melanoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Xintong Li,
  • Weinan Sun,
  • Weidong Yu,
  • Zhuo Wang,
  • Ping Sun,
  • Jianfeng Chen,
  • Haodong Li,
  • Yapeng Li,
  • Junting Ren,
  • Li Wan,
  • Rui Tang,
  • Yunpeng Wang,
  • Peng Zhao,
  • Ying Zhang,
  • Pan Li,
  • Xiaoping Leng

摘要

Background

Melanoma, the most aggressive skin cancer, remains challenging to treat due to limited therapeutic options. Sonodynamic therapy (SDT) has emerged as a promising strategy for combating malignant tumors. However, the excessive accumulation of lactate in the tumor microenvironment after SDT limits the activation of immune cells, leading to the unsatisfactory therapeutic effect of SDT. Fat mass and obesity-associated (FTO) inhibition can effectively inhibit glycolysis of melanoma cells and relieve the obstacle of immune cell activation caused by lactate. FTO inhibiting in tumors eliminates metabolic barriers to T cell activation and further enhances the antitumor effect of CD8 + T cells. Combining FTO inhibition with SDT may enhance tumor cell elimination and remodel the immunosuppressive tumor immune microenvironment.

Methods

We prepared nanoparticles through filming-rehydration method and the electrostatic adsorption method. The inhibition effects of nanoparticles on FTO and glycolysis were verified by detecting protein expression and lactate production. The therapeutic effect of nanoparticles on melanoma was evaluated by detecting the cytotoxicity of tumor cells and the infiltration of immune cells.

Results

In this study, tLyp-1 modified ultrasound phase-transforming nanoparticles loaded with sonosensitizer (Ce6) and FTO siRNA were constructed to achieve FTO inhibition and SDT. The tLyp-1 peptide modification facilitated efficient tumor targeting function and enhanced deep tissue penetration, therefore improving drug delivery efficacy. Ce6 produced reactive oxygen species (ROS) in response to ultrasound to induce immunogenic cell death (ICD) in tumor cells. At the same time, ultrasound promoted FTO siRNA transfection to inhibit B16-F10 cells glycolysis, which significantly increased the activation and infiltration of dendritic cells (DCs) and T lymphocytes in the tumor microenvironment, effectively enhanced the therapeutic effect of SDT and inhibited tumor growth.

Conclusion

This study demonstrated that si-Ce6@tLyP-1 NPs serve as a platform for targeted the tumor site and efficiently deliver siFTO and Ce6. The realization of FTO inhibition combined with SDT provides an effective treatment strategy for the treatment of melanoma.

Graphical Abstract