Targeted delivery and controlled release of deferasirox for melanoma therapy.

Melanoma, the most lethal form of skin cancer, remains a significant therapeutic challenge despite advances in immunotherapy. Although PD-1/PD-L1 blockade improves clinical outcomes, its effectiveness is frequently limited by suboptimal response rates and treatment resistance. Here, we developed a novel strategy targeting iron-dependent PD-L1 regulation. Since elevated iron activates phosphoinositide-3-kinase (PI3K)/AKT signaling and upregulates PD-L1, we employed the iron chelator deferasirox (DFX) to disrupt this pathway. To overcome DFX's poor solubility and bioavailability, we engineered tumor-targeting, glutathione-responsive albumin nanoparticles modified with cRGD peptides ((RGD)AB@DFX NPs). These NPs selectively accumulated in B16F1 melanoma tumors and released DFX in response to intracellular glutathione, effectively downregulating PD-L1. These findings suggest that iron modulation represents a promising approach to enhance immunotherapy efficacy, with (RGD)AB@DFX NPs serving as an optimized delivery platform for clinical application.