The loading and containment of cargo within nanoparticles and their efficient delivery to cells represent a primary challenge in nanomedicine. We report lipid exchange between free and mesoporous silica nanoparticle-supported lipid bilayers as an effective means of containing cargo, controlling charge, and directing delivery to mammalian cells. The delivery of a membrane-impermeable dye (calcein) and a chemotherapeutic drug (doxorubicin) are demonstrated. Exchanged lipid bilayers minimized premature drug release, and an overall positive charge on the supported lipid bilayer effected enhanced delivery.