Stabilization against fusion of zwitterionic lipid small unilamellar vesicles (SUVs) by charged nanoparticles is essential to prevent premature inactivation and cargo unloading. In the present work, we examined the stabilization of DMPC and DPPC SUVs by monolithic silica (SiO(2)) nanoparticle envelopment, for SiO(2) with 4-6, 10-20, 20-30, and 40-50 nm nominal diameter. We found that for these soft colloids stabilization is critically dependent on whether fusion occurs between the charged nanoparticles and neutral SUVs to form supported lipid bilayers (SLBs), or whether the reverse occurs, namely, nanoparticle decoration of the SUVs. While SLB formation is accompanied by precipitation, nanoparticle decoration results in long-term stabilization of the SUVs. The fate of the nanosystem depends on the size of the nanoparticles and on the ionic strength of the medium. We found that, in the case of highly charged SiO(2) nanoparticles in water, there is no SUV fusion to SiO(2) for a specific range of nanoparticle sizes. Instead, the negatively charged SiO(2) nanoparticles surround the uncharged SUVs, resulting in electrostatic repulsion between the decorated SUVs, thus preventing their aggregation and precipitation. Addition of millimolar amounts of NaCl results in rapid SLB formation and precipitation. This study has great potential impact toward better understanding the interaction of nanoparticles with biological membranes and the factors affecting their use as drug carriers or sensors.