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Temperature-sensitive amphoteric microgels with core-shell architecture are unique particles for the uptake and release of charged guest molecules. The amphoteric properties of the core-shell microgel allows binding a negatively charged polyelectrolyte under conditions such that the microgel core is positively charge while the shell is uncharged. Increasing the pH turns the microgel into a system with an anionic-shell and can also trigger the release of the bound guest from the core. We will discuss how the pH-sensitivity of core and shell control the release of synthetic polyelectrolytes and proteins from such microgels. First a poly(N-isopropylacrylamide-co-N-[3-(dimethylamino)propyl]methacrylamide) p(NIPAM-co-DMAPMA) microgel was prepared. Afterwards a cross-linked shell consisting of poly(N-isopropylacrylamide-co-dimethylitaconate) p(NIPAM-co-DMI) was added employing the ‘seed-and-feed’ method. After subsequent hydrolysis of the dimethylitaconate into itaconic acid (IA) an amphoteric core-shell microgel was obtained. Properties as, e.g. size and electrophoretic mobility, of these multi-sensitive microgels were investigated as function of pH and temperature. Sodium polystyrene sulfonates (PSSNa) of different molar mass were used as guest polyelectrolytes. PSSNa is a strong polyelectrolyte with opposite charged as compared to the microgel core. Its uptake and release was followed using UV-VIS spectroscopy as function of pH, salt concentration and polyelectrolyte chain length-size. Along the same line we studied the uptake and release of proteins. Finally we will discuss the potential of hollow microgels for uptake and release applications.