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

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 sonodynamic therapy limits the activation of immune cells, leading to the unsatisfactory therapeutic effect of SDT. FTO inhibition can effectively inhibit glycolysis of melanoma cells and relieve the obstacle of immune cell activation caused by lactic acid. FTO silencing in tumors eliminates can 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. Result In this study, tLyp-1 modified ultrasound phase-transforming nanoparticles loaded with sonosensitizer (Ce6) and FTO siRNA were constructed to achieve FTO inhibition and sonodynamic therapy. The tLyp-1 peptide modification facilitates efficient tumor targeting and enhances deep tissue penetration, therefore improving drug delivery efficacy. Ce6 produces ROS in response to ultrasound to induce 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 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 si-FTO and Ce6. The realization of FTO inhibition combined with sonodynamic therapy provides an effective treatment strategy for the treatment of melanoma.