The surface hydrophobicity of nanoparticles plays an important role in drug delivery process. The aim of this study was to verify the feasibility of using self-assembly method to prepare drug-loaded nanoparticles with tunable surface hydrophobicity. Here, Soluplus was selected as the polymeric carrier to prepare panobinostat (PNB) loaded micelles. Three different monoglycerides, glycerly monooleate (GMO), glycerly linoleate (GML) and glycerly linolenate (GMLO), were used to modify the surface of PNB-Soluplus micelles to prepare polymerlipid hybrid nanoparticles (PLHNs). The effect of monoglyceride type and amount on the physico-chemical properties of PNB-loaded PLHNs was investigated, and the surface hydrophobicity of PLHNs was characterized by Rose Bengal (RB) binding method and mucin particle method. The results suggested that compared with the PNB-Soluplus micelles (particle size 77.97±0.78 nm, zeta potential 0.44±0.29 mV, entrapment efficiency 99.45%±1.47%, the RB binding constant (K) value 0.008±0.002, the increased particle size after mixing with mucin particles 7.90±1.41 nm), surface hydrophobicity of the PLHNs increased significantly when modified by GMO, GML, GMLO, with K values of 0.055±0.010, 0.050±0.011 and 0.058±0.008, respectively. The increased particle sizes after mixing with mucin particles were 17.37±4.48 nm, 22.60±2.10 nm and 25.13±3.89 nm, respectively. Among them, the physico-chemical properties of the GMLO modified PNB-loaded PLHNs (particle size 81.60±4.52 nm, zeta potential 0.77±0.03 mV, entrapment efficiency 99.59%±0.20%) kept constant, thus GMLO was selected to further investigate the effect of GMLO mass ratio (1%-3%) to Soluplus on the properties of the nanoparticles. While no statistical significant difference in particle size, zeta potential, entrapment efficiency or in vitro release behavior was found when GMLO ratio increased, the surface lipophilicity of the PLHNs, as characterized by K values and the increased particle sizes after mixing with mucin particles, increased almost linearly with the increase of GMLO amount. In conclusion, we demonstrated that drug-loaded PLHNs based on Soluplus and GMLO can be prepared by self-assembly method, and the surface hydrophobicity was tunable by modifying the mass ratio of GMLO to Soluplus. This approach could be used for related basic science research aiming to elucidate the effect of surface hydrophobicity on in vivo behavior of drug-loaded system.