Biodegradable polymeric nanoparticles are more and more frequently used in drug delivery systems, which represent one of the most rapidly developing areas.Inourpreviousstudy,a novelnaturalhybrid polyester,polyethylene glycol 200 (PEG200) end-capped poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx-PEG) was directly produced by Aeromonas hydrophila fermentation. In this study, the performance of the novel biodegradable PHBHHx-PEG copolyester as a sustained release carrier for hydrophobic drugs with different molecular weights and the in vitro sustained release profile were investigated. 5-Fluorouracil(5-Fu, Mw=130.1), TGX221(Mw=364.4), and Rapamycin(RAP, Mw=914.2) were used as the model drugs. PHBHHx-PEG nanoparticles entrapped with 5-Fu, TGX221 and RAP were fabricated by a modified emulsification/solvent evaporation method, respectively. The average diameter of 5-Fu,TGX221, and RAP loaded PHBHHx-PEG nanoparticles was between 198.2-217.4 nm,and the entrapment efficiency of the three drugs was 62.5%, 93.4% and 91.9%,respectively. The in vitro release profiles of 5-Fu, TGX221 and RAP from PHBHHx-PEG nanoparticles were different. 5-Fu showed faster release rate and an obvious initial burst release phase. TGX221 and RAP were demonstrated to be released more slowly and steadily. The release percentages of 5-Fu, TGX221 and RAP were97.7%, 85.1% and 74.7% after releasing for 72 h. PHBHHx-PEG is a kind of promising material as a carrier for the entrapment and delivery of hydrophobic drugs especially for those drugs with high molecular weight. Biodegradable polymeric nanoparticles are more and more frequently used in drug delivery systems, which represent one of the most rapidly developing areas. In the previous study, a novel natural hybrid polyester, polyethylene glycol 200 (PEG200) end-capped poly (3-hydroxybutyrate- co- 3 -hydroxyhexanoate (PHBHHx-PEG) was directly produced by Aeromonas hydrophila fermentation. In this study, the performance of the novel biodegradable PHBHHx-PEG copolyester as a sustained release carrier for hydrophobic drugs with different molecular weights and the in vitro sustained release profile were investigated. 5-Fluorouracil (5-Fu, Mw = 130.1), TGX221 (Mw = 364.4), and Rapamycin (RAP, Mw = 914.2) were used as the model drugs. PHBHHx-PEG nanoparticles entrapped with 5-Fu, TGX221 and RAP were fabricated by a modified emulsification / solvent evaporation method, respectively. The average diameter of 5-Fu, TGX221, and RAP loaded PHBHHx-PEG nanoparticles was between 198.2-217.4 nm, and the entrapment efficiency of the thre The in vitro release profiles of 5-Fu, TGX221 and RAP from PHBHHx-PEG nanoparticles were different. 5-Fu showed faster release rate and an obvious initial burst release phase. TGX221 and RAP were demonstrated to be released more slowly and steadily. The release percentages of 5-Fu, TGX221 and RAP were 97.7%, 85.1% and 74.7% after releasing for 72 h. PHBHHx-PEG is a kind of promising material as a carrier for the entrapment and delivery of hydrophobic drugs especially for those drugs with high molecular weight.