Here, we report that carboxylated poly‐l‐lysine, a polyampholyte, shows lower critical solution temperature (LCST)‐type temperature‐responsive liquid–liquid phase separation and coacervate formation in aqueous solutions. The phase‐separation temperature of polyampholytes is strongly affected by the polymer concentration, balance between the carboxyl and amino groups, hydrophobicity of the side chain, and NaCl concentration in the solution. We concluded that the phase separation was caused by both electrostatic interactions between the carboxyl and amino groups and intermolecular hydrophobic interactions. The addition of NaCl weakened the electrostatic interactions, causing the two phases to remix. The introduction of the hydrophobic moiety decreased the phase‐separation temperature by making the molecular interactions stronger. Finally, temperature‐responsive hydrogels were prepared from the polyampholytes to explore their applicability as biomaterials and in drug delivery systems. The fine‐tuning of the phase‐separation temperature of poly‐l‐lysine‐based polyampholytes through molecular design should open new avenues for their use in precisely controlled biomedical applications. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 876–884

Stimuli-responsive materials are capable of reversibly altering their properties depending on the environmental conditions or external stimuli. External stimuli typically include thermal, pH, electric fields, optical, magnetic fields, mechanical forces and chemical interactions. There are many instances in nature where responsive surfaces have been observed. Temperature is the most widely used stimulus in environmentally responsive polymer systems. The change of temperature is not only relatively easy to control, but also easily applicable both in vitro and in vivo. Temperature responsive polymers exhibit a phase transition at a certain temperature, which causes a sudden change in the solvation state. Polymers that become insoluble upon heating have a so-called lower critical solution temperature (LCST). One example of these polymers is poly (N-isopropyl acrylamide), which shows LCST at about 32 o C, close to the physiological temperature. In this study, we report the developing of novel polyampholytes which shows thermo-, salt-responsive liquid-liquid phase separation in aqueous solution.