Doxil® is the first FDA-approved anti-cancer nano-drug. Notably, no targeted liposomal formulation has advanced to clinical stage despite tremendous work undertaken, partly due to a low stability of liposomes. Here, we report on novel lipopepsomes self-assembled from poly(ethylene glycol)-b-poly(α-aminopalmitic acid) as a stable and versatile alternative to liposomes for highly efficient encapsulation and tumor-targeted delivery of doxorubicin hydrochloride (Dox·HCl). Interestingly, lipopepsomes could be easily decorated with 20 mol% cRGD peptide and loaded with 17.4 wt% Dox·HCl, giving cRGD-LPP-Dox with a small size of ∽ 80 nm. cRGD-LPP-Dox exhibited a high stability against 10% FBS and restrained drug release under physiological conditions. Flow cytometry, confocal microscopy and MTT assays using αvβ3–overexpressing A549 tumor cells showed obviously more efficient uptake and higher anticancer activity for cRGD-LPP-Dox than for non-targeted LPP-Dox and clinically used liposomal Dox (Lipo-Dox) controls. Notably, cRGD-LPP-Dox exhibited markedly enhanced toleration and tumor accumulation than Lipo-Dox. The therapeutic studies demonstrated that cRGD-LPP-Dox achieved effective suppression of orthotopic A549 human lung tumor in nude mice, resulting in significantly improved survival rate as compared to LPP-Dox and Lipo-Dox groups. Lipopepsomes with small size, efficient loading of Dox·HCl, high stability and versatile ligand decoration have appeared as a highly attractive nanoplatform for targeted tumor chemotherapy.