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Well-defined acid-degradable amphiphilic block copolymers (ABPs) and their nanoassemblies labeled with acid-labile groups have been developed for smart drug delivery, exhibiting controlled/enhanced release of therapeutics in tumoral tissues and endo/lysosomes. In general, controlled polymerization techniques, particularly atom transfer radical polymerization (ATRP) and ring opening polymerization (ROP) have been utilized to synthesize poly(ethylene glycol)-based ABPs labeled with acetals and ketals. Despite comprehensive studies on their acid-catalyzed hydrolysis rate with substituents attached to oxygen atoms, the stability of the groups under ATRP and tin-catalyzed ROP conditions have been rarely studied. Herein, we report our investigation with benzaldehyde acetal (BzAc) as a typical acetal and cyclohexyl ketal (CyHK) as a typical ketal to understand the relationship of sensitivity to acid and stability to controlled polymerizations for acetals and ketals. Our results, along with model studies, show that BzAc is stable under ATRP, but partially stable under tin-catalyzed ROP conditions, while CyHK turns to be unstable under both ATRP and ROP conditions. Our work could provide important design principles for the synthesis of well-defined acid-degradable ABPs with respect to acid-catalyzed hydrolysis rates, thus eventually, the release rate of encapsulated drug molecules from their nanoassemblies in an acidic environment.