doi:10.1002/anie.8446184engZahid, RabiaLázaro, AriadnaMoreno-Alcántar, GuillermoSancho-Albero, MaríaPicchetti, PierreStimuli‐responsive silsesquioxane nanozymes for organocatalysis in water and prodrug activation in cellsART-2026-148895Synthetic 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.2026http://zaguan.unizar.es/record/17039810.1002/anie.8446184http://zaguan.unizar.es/record/170398oai:zaguan.unizar.es:170398info:eu-repo/grantAgreement/ES/AEI/PID2023-148732NB-I00info:eu-repo/grantAgreement/EUR/COST/CA22131-LUCESinfo:eu-repo/grantAgreement/ES/MICIU/RYC2024-050017-IAngewandte Chemie (International ed.) (2026), e8446184 [11 pp.]byhttps://creativecommons.org/licenses/by/4.0/deed.esinfo:eu-repo/semantics/openAccess