We developed one-step self-assembly method to prepare poly(ethylene glycol)-phosphatidylethanolamine (PEG-PE) micelles, which had core-shell structure and particle size at 20 nm. Drug-loaded PEG-PE micelles displayed better stability than empty micelles in vitro and in vivo because the drug/polymer interactions reinforced the micellular structure. Drugs distributed at the core-shell interface of PEG-PE micelles without changing micellar size. Our studies demonstrated that physico-chemical properties of drugs determined their self-assembly mechanism with polymers and the release profiles of drugs from micelles in vitro. Encapsulation of drugs in micelles increased their cellular accumulation due to the increased membrane fluidity caused by PEG-PE insertion, which did not affect cell membrane permeability and integrity. Compared to free drugs, anticancer drugs encapsulated into PEG-PE micelles demonstrated an increased antitumor efficiency in vivo and an extended life span of mice by EPR effect of PEG-PE micelles. On the other hand, PEG-PE micelles maintained higher drug concentrations in lymphatic systems, thus resulting in significantly antitumor effects for metastatic tumors with less lung metastasis. PEG-PE is an FDA-approved nonionic diblock copolymer with good biocompatibility and safety. As drug delivery systems, PEG-PE micelles has a wide developmental future.