A core-shell structured synthetic carrier, polywraplex, is reported to overcome the hurdles along the inter-and intracellular pathways of systemic delivery of siRNA, yet remain structurally simple and easy-to-formulate. The core is a cationic polyplex formed of siRNA with polyethylene imine (PEI) and polyspermine-imidazole-4,5-imine (PSI), respectively, and the shell is a self-assembled unilamella membrane of PEG(45)-PCL20-mototriose-COO-, a triblock copolymer possessing multicarboxyl saccharide block to guide adsorption to each polyplex surface, a hydrophobic central block to form a protecting layer around the nucleic acid core, and a PEG block functioning as a steric stabilization out-layer to extend in vivo circulation. The hydrophobic layer limits the anionic charges of the guiding block within a 2D surface to prevent them from penetrating into the polyplex, a common cause for prephagocytic siRNA leaking by polyelectrolytes in vivo. Cell targeting agents may be conjugated to the distal end of the PEG block and assembled on polyplex surface in optimal population. Chemical characterizations comprising consequent fluorescent imaging, dynamic laser scattering, zeta potential, as well as electrophoresis confirm polywraplex formation and its protection to siRNA against leaking and degradation in serum. Cellular and in vivo (mice) assays of biotin-conjugated polywraplexes suggest prolonged circulation and tumor tissue targeting.