Lipid nanovesicles (LNVs) and polymer nanovesicles (PNVs), also known as liposomes and polymersomes, are becoming increasingly vital in global health. However, the two major classes of nanovesicles both exhibit their own issues that significantly limit potential applications. Here, by covalently attaching a naturally occurring phosphate "lipid head" and a synthetic polylactide "polymer tail" via facile ring-opening polymerization on a 500 g scale, a type of "chimeric" nanovesicles (CNVs) can be easily produced. Compared to LNVs, the reported CNVs exhibit reduced permeability for small and large molecules; on the other hand, the CNVs are less hydrophobic and exhibit enhanced tolerance toward proteins in buffer solutions without the need for hydrophilic polymeric corona such as poly(ethylene glycol)(PEG), in contrast to conventional PNVs. The proof-of-concept in vitro delivery experiments using hydrophilic solutions of fluorescein-PEG, rhodamine-PEG, and anti-cancer drug doxorubicin demonstrate that these CNVs, as a structurally diverse class of nano-materials, are highly promising as alternative carriers for therapeutic molecules in translational nanomedicine.