The invention belongs to the field of pharmaceutic preparations, and relates to a targeted ligand-PEG (polyethylene glycol)-cholesterol/tocopherol derivative, and a preparation method and an application of the derivative, in particular to an application of the derivative in a composite mechanism mediate tumor targeted drug delivery system. According to the derivative, the preparation method and the application, a drug delivery system consisting of the targeted ligand-PEG-cholesterol/tocopherol derivative with a targeting function, a long circulating function and a pH (power of hydrogen) sensitive function as a functional material, a cation liposome and a drug can simultaneously carry anticancer polypeptide and gene/chemotherapy drugs. According to the system, different drugs are jointly entrapped into the lipid nano drug delivery system and delivered into a targeted cell by utilizing a physicochemical property difference between components or by in-vivo specific targeted recognition, signal conduction blocking and pH triggering PEG chain breaking charge reversion methods, so that a targeted tumor therapeutic effect is improved. According to the derivative, the preparation method and the application, the advantages of the system in directional delivery, co-delivery and the like are proved by in-vivo and in-vitro activity evaluation, the anticancer activity is improved significantly, and definite synergic therapeutic and immunity effects are provided.