doi:10.1002/cctc.70141engMosseri, AndreaRueda-Flores, AnaHueso, Jose L.Urriolabeitia, EstebanDe Cola, LuisaSantamaria, JesusGlutathione Threshold‐Triggered Selective Breakability of Organosilica NanocapsulesART-2025-144942Biomolecules like proteins and enzymes can target and disrupt cancer cell pathways more specifically and with lower toxicity than traditional treatments. However, their lack of stability and methods for their effective delivery still present unsolved challenges. Silica nanocapsules have been proposed as carriers capable of protecting sensitive loads but their use is limited by their low biodegradability. For this reason, breakable silica structures, able to disassemble when exposed to representative levels of biomolecules readily available in the tumor microenvironment (TME), appear as ideal delivery vectors. In this work, we focus on the optimization of the synthesis parameters governing the breakability of organo‐silica nanocapsules containing cleavable disulfide bonds. The objective is to trigger selective release in the presence of glutathione (GSH), a key molecule overexpressed in tumor cells. However, disulfide bonds can also be degraded in the presence of other molecules, which reduces the selectivity of delivery. We have modified the synthesis to obtain a response that leads to silica disassembly only when GSH levels are above a certain threshold, while remaining stable against other reductants, such as those present in standard extracellular culture media. The selection of the proper silica precursor was critical to obtain silica capsules that is able to disassemble and release Cytochrome C (CytC) upon exposure to GSH concentrations typical of those existing in the TME.2025http://zaguan.unizar.es/record/16227210.1002/cctc.70141http://zaguan.unizar.es/record/162272oai:zaguan.unizar.es:162272info:eu-repo/grantAgreement/ES/AEI/CEX2023-001286-Sinfo:eu-repo/grantAgreement/ES/AEI/PID2023-148732NB-I00info:eu-repo/grantAgreement/EC/H2020/964386/EU/A key to the rational design of extracellular vesicles-mimicking nanoparticles/MIMIC-KeYThis project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 964386-MIMIC-KeYChemCatChem (2025), e01931 [9 pp.]by-nchttps://creativecommons.org/licenses/by-nc/4.0/deed.esinfo:eu-repo/semantics/openAccess