Synthetic nanozymes have emerged as promising alternatives to natural enzymes for catalytic and therapeutic applications, yet their limited stability, aqueous compatibility, and catalytic scope impede broader utilization. Here, we report a mild, one-step sol–gel synthesis that yields ultrasmall, water-stable octa-amino silsesquioxanes functioning as metal-free nanozymes. These minimalistic nanostructures exhibit aldolase-like organocatalytic activity in water and enable dynamic, stimuli-responsive modulation of catalysis through reversible supramolecular aggregation and disaggregation triggered by specific chemical inputs, thus forming a multifunctional platform for tunable catalysis and biomedical applications. Structural simplicity, stability, and functional versatility together permit tunable, enzyme-like catalysis in water without auxiliary surfactants or phase-transfer additives. Furthermore, the nanozymes display high biocompatibility and efficient cellular internalization, enabling their use in living cells, for instance, as intracellular prodrug activators via retro-aldol activation of a doxorubicin prodrug in human glioblastoma and metastatic melanoma cells, resulting in selective cytotoxicity. This system provides a cost-effective, sustainable, and scalable platform for water-compatible, metal-free organocatalysis that bridges abiotic catalysis and biological function. These findings demonstrate how rationally designed silsesquioxane frameworks can emulate natural enzyme reactivity while integrating adaptive, stimuli-responsive behavior, broadening the applicability of synthetic nanozymes to catalytic and therapeutic contexts.
Zahid et al. (Thu,) studied this question.