DuoLipo-TNP: Dual-Responsive Liposome Platform for Selective Delivery of Triphosphate Nucleotide Prodrugs in Triple-Negative Breast Cancer

Breast cancer is the most frequently diagnosed cancer in women worldwide and a leading cause of cancer mortality in Europe, with triple-negative breast cancer (TNBC) representing the most aggressive and therapy-resistant subtype. Driven by tumor heterogeneity, poor vascularization, and a hostile microenvironment, TNBC urgently requires new therapeutic strategies, an unmet clinical need directly aligned with the EU Mission on Cancer. DuoLipo-TNP seeks to address these challenges by developing dual-responsive liposomal nanocarriers for the selective delivery of γ-masked triphosphate nucleotide prodrugs (TNPs). The platform combines tumor-penetrating iRGD peptides for αvβ3/αvβ5 integrin-mediated vascular targeting with lipid components responsive to hypoxia and acidic pH, two hallmark features of TNBC. This dual-triggered strategy enables site-specific release of active antimetabolites, bypasses kinase-dependent activation, and minimizes systemic toxicity. The project applies a multidisciplinary approach spanning prodrug synthesis, advanced liposomal formulation and characterization, and comprehensive pharmacological validation in 2D and 3D TNBC models, including patient-derived spheroids. Ultimately, DuoLipo-TNP aims to establish a platform for intratumoral delivery of nucleotide analogues, advancing precision nanomedicine and contributing to the EU Mission on Cancer by improving outcomes in drug-resistant solid tumors.