Dual chemohormonal silver–tamoxifen nanosystem for targeted therapy of ER+ breast cancer: Multi-omics mechanistic insights and in vivo validation

The development of novel anticancer agents remains crucial to improve therapeutic efficacy while minimizing adverse effects. Nanomaterials offer an attractive strategy to achieve this goal, as they enable the co-delivery of multiple cytotoxic agents in a targeted and controlled manner. In this study, a previously designed core–shell nanosystem composed of a silver core coated with mesoporous silica nanoparticles and functionalized with transferrin (Tf) as a targeting ligand was optimized through the incorporation of the antitumor drug tamoxifen (TMX) into the mesoporous silica matrix. This design strategically combines a chemotherapeutic (Ag) and a hormonal (TMX) component within a single nanoplatform, enabling a dual-mode antitumoral strategy against ER + breast cancer cells. Comprehensive characterization demonstrated selective internalization of the Ag@MSNs–TMX–Tf nanosystem by estrogen receptor-positive (ER + ) breast cancer cells overexpressing transferrin receptors, together with enhanced cytotoxic activity compared to the TMX-free nanosystem. To elucidate the molecular mechanisms underlying its antitumor effect, a multi-omics approach combining SILAC-based quantitative proteomics with targeted and untargeted metabolomics was employed. This integrative analysis revealed that the nanosystem affects key cellular pathways related to proliferation, migration, DNA replication, and energy metabolism. Finally, in vivo evaluation using the chicken embryo model confirmed the superior antitumor efficacy of the TMX-loaded nanosystem in a complex biological environment. Overall, the results highlight the synergistic interaction between hormonal and chemotherapeutic components, supporting the potential of the Ag@MSNs–TMX–Tf nanosystem as a promising platform for targeted therapy of ER + breast cancer.