Biodegradable polyesters such as poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), and poly(ε-caprolactone) (PCL) have been widely utilized as biomaterials, particularly in drug delivery systems. Traditional nanoparticle preparation methods mainly use a two-step emulsion and solvent evaporation process, which requires water-immiscible volatile solvents. However, this study introduced an alternative approach employing film hydration and ultrasonication, enabling water-miscible volatile solvents and thus expanding the range of drugs that can be incorporated into nanoparticles. The resulting low molecular weight polyester nanoparticles (polyester-NP:U) exhibited physicochemical characteristics, including size, zeta potential, surface hydrophobicity, and colloidal stability, that were significantly influenced by the concentration and molecular weight (MW) of PCL. Furthermore, a spectrum of hydrophobic payloads in the low molecular weight polyester-NP:U could be extened, such as doxorubicin (DOX), paclitaxel (PTX), kaempferol (KAE), curcumin (CUR), 5-fluorouracil (5-FU), and fargesin (FAR).