The objective of this study was to design shear-sensitive fattigation-platform albumin nanoparticles to release the cargo at a high shear stress sites. Sodium docosahexaenoic acid (DHA) was chosen as a fatty acid of fattigation-platform. Using 1-Ethyl-3-(3-aminopropyldimethyl) carbodiimide (EDC), the sodium DHA was conjugated with human serum albumin (HSA) via carbodiimide reaction. The different types of HSA-DHA nanoparticles were prepared via desolvation method using fattigation-platform for design shear-sensitive nanoparticles. The sodium DHA fatty acid which had a long carbon chain (C22) was selected to prepare to loose structure of fattigation nanoparticles and successfully conjugated with HSA. To make more shear-sensitive nanoparticles, HSA-DHA nanoparticles were prepared by adding polymer, polyethylenimine (PEI), which can weakly electrostatic interact with albumin. The physicochemical properties of HSA-DHA nanoparticles were identified using ATR FTIR, DLS, SEM. Drug loading capacity of these nanoparticles showed high drug loading content and encapsulation efficiency. Biomimetic microfluidic system (BMS) was established to evaluate the shear-sensitive response of the nanoparticles. The shear-sensitivity of HSA-DHA nanoparticles were evaluated using UV-vis turbidity to detect disintegration of nanoparticles and shear induced drug release. The HSA-DHA with PEI nanoparticles had great shear sensitivity compared to other HSA-DHA nanoparticles at a high shear stress. In our findings, the shear-sensitive fattigation-platform nanoparticles could be designed to release the cargo at a specific shear stress site such as stenosis and thrombosis in blood vessels.