In this study, the advanced liposomal spherical nucleic acid (L-SNA) is exploited for the first time to establish a spherical, three-dimensional biosensing platform by hybridizing with a set of nanoparticles. By hydrophilic and hydrophobic interactions as well as programmable base-pairing, red-emission quantum dots (QDs), green-emission QDs, and gold nanoparticles (AuNPs) are encapsulated into the internal aqueous core, the intermediate lipid bilayer, and the outer SNA shell, respectively, producing an L-SNA–nanoparticle hybrid. As a result of the site-selective encapsulation, the hybrid constitutes a liposomal fluorescent “core–resonance energy transfer” system surrounded by a SNA shell, as is imaged at the single-particle resolution by confocal microscopy. With the outer SNA shell as three-dimensional substrate for duplex-specific nuclease target recycling reaction, the hybrid is capable of amplified detection of microRNAs, featuring one target to many AuNP-manipulated, dual-emission QD-based ratiometric fluorescence. More importantly, the ratiometric fluorescence facilitates the hybrid to visualize microRNAs with remarkably high resolution, which is exemplified by traffic light-type transition in fluorescence color for diagnosing circulating microRNAs in clinical serum samples. Substantially, the controllable hybridization with functional nanoparticles opens an avenue for the exciting biomedical applications of liposomal spherical nucleic acids.