A biocompatible core–shell nanocapsule is fabricated to target tumor vascular endothelial cells where it releases anti-angiogenesis and anticancer drugs sequentially. The fabrication of the core–shell nanocapsule is accomplished through a robust double self-assembly procedure: the hydrophobic polymeric core is first precipitated to encapsulate a poorly water-soluble anticancer drug paclitaxel (PTX) with the assistance of lecithin and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)2000] (DSPE-PEG) self-assembled in aqueous phase. Another lipid layer self-assembled around the above hydrophobic core is formed to load a second drug combretastatin A4 (CA4) as a vascular disrupting agent in the lipid layer. The lipid layer serves both as a depot for CA4, as well as a molecular fence to sustain the release of PTX from the polymeric core. The size of the resultant nanocapsule can be fine-turned by slightly adjusting the preparation conditions from several tens of nanometer to one hundred nanometers. The uptake of this nanocapsule by human umbilical vein endothelial cells (HUVEC) is efficient, and the two loaded drugs maintain their respective therapeutic potency. The time-dependent sequential release of these two drugs over a time difference of 36 h results in temporal ablation of endothelial cells and cancer cells. This self-assembled delivery system could serve as a universal prototype that can be applied for other combinatorial temporal drug delivery.