Polyhedral Oligomeric Silsesquioxane (POSS)-F68 hybrid vesicles with an average diameter of 700 nm are produced using a stable solution of heterofunctional POSS having 3-aminopropyl and vinyl groups and pluronic F68 in ethanol-water mixture. Thermogram and zeta potential values evidence the spontaneous self-assembly of POSS into bilayers through H-bonding interaction between the aminopropyl groups, and the effective stabilization of the POSS-bilayers by amphiphilic F68 during solvent-evaporation to form the vesicles. The vesicles are noncytotoxic and dispersible in aqueous solvents through steric stabilization provided by the hydrophilic F68. A highly facile coinclusion method has been used for making doxorubicin and folic acid loaded vesicles. Doxorubicin loaded in the vesicles exhibits a controlled release profile in phosphate buffered saline. Confocal microscopic and flow cytometric studies on the endocytosis of the vesicles by HeLa and HOS cells prove that a noncovalent entrapment of excess folic acid in the vesicles through H-bonding is sufficient to enhance the uptake significantly. POSS-F68 vesicles in combination with folic acid and a chemotherapeutic can have potential for targeted intracellular anti-cancer drug delivery.