Paclitaxel (PTX) is successfully loaded by surface modification of distearoyl phosphoethanolamine (DSPE) on halloysite nanotubes (HNTs) with different inner lumen diameters. Drug loading of DSPE-HNTs-PTX attains 18.44% of DSPE content with a nearly complete release (near 100%) achieved. The anticancer efficacy (cell viability less than 52%) of DSPE-HNTs15-PTX increased and is attributed to the lower interfacial energy both inside and outside the tubes that improves tube loading.