The purpose of this work was to develop a novel picropodophyllin-loaded micelle-like nanoparticle with a biodegradable amphiphilic star-shaped polycaprolactone-polyethyleneglycol copolymer (S-PCL-PEG). S-PCL-PEG was synthesized using star-shaped polycaprolactone (S-PCL) as a hydrophobic block and monomethoxy polyethyleneglycol (PEG) as a hydrophilic block and characterized by 1H-NMR. It was confirmed by the pyrene fluorescence probe method that the obtained S-PCL-PEG could form micelles through self-assembly in aqueous media. In addition, picropodophyllin (PPP), a hydrophobic anticancer drug, could be entrapped in the hydrophobic inner core of the micelles using the thin film hydration method, forming PPP-loaded micelle-like nanoparticles (PPP-NPs). PPP-NPs had a high encapsulation efficiency of greater than 90%, an average size of 90-110 nm with a symmetrical monodisperse distribution and a zeta potential of -18 mV. Additionally, in vitro release tests showed that approximately 70% of the drug was released from PPP-NPs into PBS (pH 7.4) containing 0.2% Tween 80 at 37 degrees C for 96 h, and the drug release data fit well to the Higuchi equation. Furthermore, an in vitro tumor cell growth inhibition assay showed that the IC50 values of the PPP solution and PPP-NPs against SMMC7721 liver cancer cell lines were 0.4 microg/ml and 0.2 microg/ml respectively, which indicated that the cytotoxicity of PPP-NPs against tumor cells was greater than that of the PPP solution. In conclusion, S-PCL-PEG micelle-like nanoparticles loaded with PPP have a promising future for administration by injection.