The recent nanomedicine advancements have introduced a variety of smart nanoparticles in cancer treatment and diagnostics. However, their application to the clinic is still hindered by several challenges related to their biocompatibility, elimination and biodistribution. Here we propose breakable organosilica mesoporous nanoparticles, i.e. nanocages, able to efficiently incorporate cargo molecules and be coated, with different lipid compositions, to enhance their biomimetic behaviour. We exploit the electrostatic interactions between the organosilica surface and the opposite charge of the lipid mixtures in order to obtain an efficient organosilica coverage. The lipid-coated nanocages are proved to have an incredibly high hemocompatibility, significantly increased with respect to pristine nanocages, and excellent colloidal stability and biocompatibility. The cargo-loaded and lipid-coated nanocages are tested and compared in vitro on two different cancer cell lines, demonstrating the key role played by the lipid coating in mediating the internalization of the nanocages, evaluated by the enhanced and rapid cellular uptake. The efficient intracellular delivery of the therapeutic agents is then assured by the destruction of the organosilica, due to the disulfide bridges, introduced into the silica framework, that in reducing media, like the intracellular one, are reduced to thiols causing the breaking of the nanoparticles. The possibility to image and effectively kill cancer cells demonstrates the potentiality of the lipid-coated nanocages as a powerful tool in anticancer research and as a promising smart theranostic platform.