Design and fabrication of smart liquid quantum dots (LQDs) with high biomolecule selectivity and specificity remains a challenge. Herein, a multifunctional calix[4]arene derivative (PCAD) was rationally designed and applied to fabricate a Tyr-responsive CdSe-LQD system through host-guest chemistry. Such a biosensor displays an outstanding fluorescence/macroscopic response for Tyr and reversible fluidic features due to the hydrogen interaction between the PCAD of CdSe-LQDs and Tyr. These excellent results highlighted CdSe-LQDs as a promising platform for biological molecule recognition and separation in the future.