As we explored SIE2 as a platform for the controlled release of therapeutic agents, we found that this platform necessitates a phenol group as the leaving group. A model compound SIE4 containing an alcoholic leaving group was essentially inert under our experimental conditions (Figure , Figure ). The difference in reactivity between SIE2 and SIE4 can be explained by the electron-withdrawing effect of the benzene that stabilizes the putative phenolate anion, lowering the energy barrier of the reaction. Consequently, we advanced the SIE structure by incorporating a 4-hydroxybenzyl alcohol linker as a leaving group (as illustrated by SIE5, Figure ), allowing for the modular conjugation of different functional molecules and their release through a well-established 1,6-elimination mechanism. As a proof-of-concept demonstration, we chose to encapsulate methylene blue (MB, an FDA-approved agent for methemoglobinemia and a well-known photosensitizer) as a therapeutic payload in SIE5 (Figure ). SIE5 was designed to undergo a cyclization-elimination cascade and release an MB-precursor (Figure ), which spontaneously oxidizes to form MB. The successful MB release from SIE5 (16 µM in pH 6.5 MES, 37°C) was supported by the emergence of its characteristic absorption peak around 665 nm (Figure ), with an estimated reaction half-life of 9 h (Figure , square). However, we found that, quantitatively, the concentration of released MB was limited to approximately 60% of the theoretical yield even after prolonged incubation. To fully understand the reaction, a MES solution of SIE5 was incubated at 37 °C for three days, extracted by copious dichloromethane, and then the extract was concentrated and separated through silica gel chromatography. We analyzed the reaction products by NMR and mass spectrometry (Figure , Figure ) and identified a major byproduct BP1 (isolated yield = 37%), which could be explained as the 1,6-elimination intermediate of the 4hydroxybenzyl alcohol linker, the quinone methide, reacted with the nucleophilic amine group in SIE5.