Botulinum neurotoxins (BoNTs)， the most potent toxins known， are potential bioterrorism agents. It is well established that all seven serotypes of BoNTs (BoNT/A-G) require complex gangliosides as co-receptors. Here， we report that BoNT/DC， a presumed mosaic toxin between BoNT/D and BoNT/C1， binds and enters efficiently into neurons lacking complex gangliosides and shows no reduction in toxicity in mice deficient in complex gangliosides. The co-crystal structure of BoNT/DC with sialyl-Thomsen-Friedenreich antigen (Sialyl-T) suggests that BoNT/DC recognizes only the sialic acid， but not other moieties in gangliosides. Using liposome flotation assays， we demonstrate that an extended loop in BoNT/DC directly interacts with lipid membranes， and the co-occurring sialic acid binding and loop-membrane interactions mediate the recognition of gangliosides in membranes by BoNT/DC. These findings reveal a unique mechanism for cell membrane recognition and demonstrate that BoNT/DC can use a broad range of sialic acid-containing moieties as co-receptors.