The purpose of this study was to engineer nanoparticles with various sustained profiles of drug release and prolonged circulation by blending poly(D,L-lactic acid)/poly(D,L-lactic/glycolic acid) (PLA/PLGA) homopolymers and poly(ethylene glycol) (PEG)-block-PLA/PLGA copolymers encapsulating betamethasone disodium 21-phosphate (BP). Nanoparticles of different sizes, drug encapsulation/release profiles, and cellular uptake levels were obtained by mixing homopolymers and block copolymers with different compositions/molecular weights at various blend ratios by an oil-in-water solvent diffusion method. The in vitro release of BP increased with nanoparticles of smaller size or of PLGA homopolymers instead of PLA homopolymers. Furthermore, the uptake of nanoparticles by macrophage-like cells decreased with nanoparticles of higher PEG content, and nanoparticles of PEG-PLGA block copolymers were taken up earlier than those of PEG-PLA block copolymers after incubation with serum. In addition, prolonged blood circulation was observed with nanoparticles of smaller size with higher PEG content, and nanoparticles of PEG-PLA block copolymers remained longer in circulation than those of PEG-PLGA block copolymers. Analysis of BP concentration in organs revealed reduced liver distribution of blended nanoparticles compared with PLA nanoparticles. This is the first study to systematically design and characterize biodegradable PLA/PLGA and PEG-PLA/PLGA-blended nanoparticles encapsulating BP with different release profiles and stealthiness.