Core-shell nanoparticles made of a maghemite core and a mesoporous silica shell were developed as drug delivery systems (DDS). Doxorubicin® (DOX, DNA intercalating drug) was loaded within the mesoporous cavities, while phase-change molecules (PCMs), e.g. 1-tetradecanol (TD) with a melting temperature (Tm) of 39 °C, were introduced as gatekeepers to regulate the release behaviours. An overall loading amount of ca. 20 wt% (TD/DOX ca. 50/50 wt/wt) was confirmed. Heat-triggered release of DOX evidenced a "zero premature release" (<3% of the entire payload in 96 h release) under physiological conditions (37 °C), and however, a sustainable release (ca. 40% of the entire payload in 96 h) above Tm of TD (40 °C). It also demonstrated the possibility to deliver drug payloads in small portions (pulsatile release mode) via multiple heating on/off cycles, due to the reversible phase change of the PCMs. In vitro heat-triggered release of DOX within cell culture of the MEL-5 melanoma cell line was also tested. It was found that DOX molecules were trapped efficiently within the mesopores even after internalization within the cytoplasm of MEL-5 cells at 37 °C, with the potential toxicity of DOX strongly quenched (>95% viability after 72 h incubation). However, continuous cell apoptosis was detected at cell culture temperature above Tm of TD, due to the heat-triggered release of DOX (<50% viability after 72 h incubation at 40 °C). Moreover, due to the presence of a maghemite core within the DDS, T2-weighted magnetic resonance imaging performance was also confirmed. These as-designed core-shell nanoparticles are envisaged to become promising DDS for "on-demand" heat-triggered release.< Réduire