One　challenge　for　daidzein　delivery　is　how　to　efficiently　suppress　its　precipitation/crystallization　in　a　lipid-based　system.　In　this　work,　whey　protein　isolate　(WPI)　with　different　thermal　treatment　was　employed　as　a　hydrophobic　drug　crystallization　depressor　and　its　interaction　mechanism　with　daidzein　was　studied.　The　results　indicated　WPI　aggregated　to　form　nanoparticles　(below　300　nm)　in　the　presence　of　daidzein.　Thermal　denaturing　(85　°C,　20　min)　improved　the　binding　affinity　for　daidzein　with　Ka　=　1.165　×　10　4　M　−1　,　about　1.5-fold　higher　than　that　of　the　native　protein　(Ka　=　7.285　×　10　3　M　−1　).　Hydrophobic　interaction　was　the　major　driving　forces　based　on　thermodynamic　calculation.　The　as-obtained　protein-based　nanocomplexes　efficiently　inhibited　daidzein　crystallization,　enhancing　its　solubility　at　least　2-fold　with　promoted　stability　(stable　at　4　°C　for　at　least　2　months).　These　findings　provide　new　ideas　for　the　application　of　WPI,　showing　great　potential　to　be　directly　used　in　lipid　nanocarrier　system　as　crystallization　depressor.　©　2018　Elsevier　Ltd