Natural esterases hydrolyze esters under physiological pHs but chemists often have to use strongly acidic or basic conditions for the same hydrolysis. We report synthetic nanoparticle catalysts that hydrolyze nonactivated alkyl esters at room temperature and neutral pH, with enzyme-like catalytic mechanisms and exquisite substrate selectivity. Unlike natural enzymes that denature easily at elevated temperatures, the synthetic catalysts become more active at higher temperatures.