Smart lipids with fluorescence emission, thermal response, and polyethylene glycolation (PEGylation) functions can be highly valuable for formulation, image-traceable delivery, and targeted release of payloads. Herein, a series of jellyfish-shaped amphiphiles with a tetraphenylethene (TPE) core and four symmetrical amphiphilic side chains were conveniently synthesized and systematically investigated as smart lipids. Compared with regular amphiphilic TPEs and phospholipids, the unprecedented jellyfish-shaped molecular geometry was found to enable a series of valuable capabilities, including sensitive and responsive aggregation-induced emission of fluorescence (AIE FL) with high quantum yields, efficient encapsulation of drugs into stable nanoparticles, PEGylation of nanoparticles with thermally responsive drug release, and real-time FL monitoring of drug uptake. Furthermore, the jellyfish-shaped geometry facilitated the concentration-dependent aggregation of unimolecular micelles into “side-by-side” assembled nanoparticles with a unique mode of AIE. In addition, the size and the arrangement of the amphiphilic side chains were found to dominate the aggregate stability, cell uptake, and thus the cytotoxicity of the amphiphiles. The study has unprecedentedly developed versatile smart TPE lipids with precise structures, unique physicochemical and biological properties, and great potential in biomedicine, which peculiar structure-property relationship may shed new light on the design and application of AIE fluorophores and functional lipids in biomedicine and materials science.