The effect of structural variations in acetal- and ketal-based linkers upon their degradation kinetics is studied through the design, synthesis, and study of six series of molecules, comprising a total of 18 different molecules. Through this systematic study, we show that the structural fine-tuning of the linkers allows access to variations in kinetics of degradation of more than 6 orders of magnitude. Hammett correlations show that the p value for the hydrolysis of benzylidene acetals is about -4.06, which is comparable to an S(N)1-like process. This shows that there is a strong, developing positive charge at the benzylic position in the transition state during the degradation of acetals, This positively charged transition state is consistent with the relative degradation rates of acetals vs ketals (correlated to stabilities of 1 degrees, 2 degrees, and 3 degrees carboxonium ion type intermediates) and the observed effect of proximal electron-withdrawing groups upon the degradation rates. Following this, we studied whether the degradation kinetics study correlates with pH-sensitive variations in the host guest characteristics of polymeric nanogels that contains these acetal ketal moieties as cross-linking functionalities. Indeed the trends observed in the small molecule degradation have clear correlations with the encapsulation stability of guest molecules within these polymeric nanogels. The implications of this fundamental study extend to a broad range of applications, well beyond the polymeric nanogel examples studied here.