Chemical construction of molecularly organic inorganic hybrid hollow mesoporous organosilica nano-particles (HMONs) with silsesquioxane framework is expected to substantially improve their therapeutic performance and enhance the biological effects beneficial for biomedicine. In this work, we report on a simple, controllable, and versatile chemical homology principle to synthesize multiple-hybridized HMONs with varied functional organic groups homogeneously incorporated into the framework (up to quintuple hybridizations). As a paradigm, the hybridization of physiologically active thioether groups with triple distinctive disulfide bonds can endow HMONs with unique intrinsic reducing/acidic- and external high intensity focused ultrasound (HIFU)-responsive drug-releasing performances, improved biological effects (e.g., lowered hemolytic effect and improved histocompatibility), and enhanced ultrasonography behavior. The doxorubicin-loaded HMONs with concurrent thioether and phenylene hybridization exhibit drastically enhanced therapeutic efficiency against cancer growth and metastasis, as demonstrated both in vitro and in vivo.