Defeating Melanoma Through a Nano-Enabled Revision of Hypoxic and Immunosuppressive Tumor Microenvironment.

Rationale: Reversing the hypoxic and immunosuppressive tumor microenvironment (TME) is crucial for treating malignant melanoma. Seeking a robust platform for the effective reversion of hypoxic and immunosuppressive TME may be an excellent solution to revolutionizing the current landscape of malignant melanoma treatment. Here, we demonstrated a transdermal and intravenous dual-administration paradigm. A tailor-made Ato/cabo@PEG-TK-PLGA NPs were administrated transdermally to melanoma with the help of a gel spray containing a skin-penetrating material borneol. Nanoparticles encased Ato and cabo were released and thereby reversed the hypoxic and immunosuppressive tumor microenvironment (TME). Methods: Ato/cabo@PEG-TK-PLGA NPs were synthesized through a self-assembly emulsion process, and the transdermal ability was assessed using Franz diffusion cell assembly. The inhibition effect on cell respiration was measured by OCR, ATP, and pO Results: The transdermally administrated Ato/cabo@PEG-TK-PLGA NPs successfully spread to the skin surface of melanoma and then entered deep inside the tumor with the help of a gel spray and a skin puncturing material borneol. Atovaquone (Ato, a mitochondrial-respiration inhibitor) and cabozantinib (cabo, a MDSCs eliminator) were concurrently released in response to the intratumorally overexpressed H Conclusion: Taken together, we developed a transdermal and intravenous dual-administration paradigm, which effectively reversed the hypoxic and immunosuppressive tumor microenvironment in the treatment of the malignant melanoma. We believe our study will open a new path for the effective elimination of the primary tumors and the real-time control of tumor metastasis.