Silver-selenium hybrid nanocomposite with combined cytotoxic and metabolic reprogramming effects in triple-negative breast cancer

Triple-negative breast cancer (TNBC) remains one of the most aggressive breast cancer subtypes due to its high metastatic potential, poor response to conventional therapies, and frequent relapse after chemotherapy. In this work, we report a novel hybrid nanosystem that integrates, within a single mesoporous silica nanoplatform, two inorganic nanoparticles with complementary antitumoral activities: silver nanoparticles confined inside a mesoporous silica shell and selenium nanoparticles nucleated on the external surface. The core@shell Ag@MSN nanosystem was functionalized with transferrin to guide selective uptake by cancer cells which moreover provides the protein matrix required for controlled selenium nanoparticle growth, yielding the final Ag@MSN-Tf-SeNPs nanocomposite. The nanosystem was thoroughly physicochemically characterized and biologically evaluated in MDA-MB-231 TNBC cells. Ag@MSN-Tf-SeNPs showed efficient and selective internalization mediated by transferrin receptors and displayed a markedly enhanced cytotoxic effect resulting from the combined action of Ag and Se. Cell-cycle analysis revealed G0/G1 arrest accompanied by a strong induction of apoptosis. To unravel the underlying bioactivities, an untargeted mass spectrometry-based metabolomics assay demonstrated profound metabolic disruption, including altered fatty-acid metabolism, impaired TCA cycle activity, and suppression of key biosynthetic pathways essential for TNBC survival. Finally, the antitumoral efficacy of the nanosystem was validated in vivo using a chicken chorioallantoic membrane model, where Ag@MSN-Tf-SeNPs significantly reduced tumor mass. Overall, this study presents a novel Ag-Se hybrid silica nanocomposite with selective tumor cells targeting, combined mechanisms of action, and potent antitumoral activity, highlighting its promise as a therapeutic platform for TNBC.