Synthesis, characterization and controlled release behavior of a new hybrid material based on silica mesoporous nanoparticles caped with a self-immolative gate is reported.There is a significant interest in the development of methodologies of controlled release for a diverse range of applications. [1] For this reason, a large diversity of drug nanocarriers having different size, structure and surface properties, such as liposomes and polymeric or inorganic nanoparticles, have been developed over the last decades. [2] Among these, mesoporous silica nanoparticles (MSNs) have attracted great attention in recent years due to their unique features such as stability, biocompatibility, large load capacity and the possibility of easy functionalizing their surface to obtain targeting and drug release systems. [3] In this scenario, an appealing concept when using MSNs is the possibility to functionalize the external surface with gated ensembles. The development of gated systems able to retain the payload yet releasing it upon the presence of a predefined stimulus has been proved to be an excellent approach to develop advanced nanodevices for controlled delivery applications. [4] In fact, through decoration of the mesoporous material with a wide collection of organic and biological entities or inorganic capping agents, researchers have prepared recently gated MSNs that can be triggered by target chemical (such as selected anions, cations neutral molecules, redox-active molecules, pH changes and biomolecules), physical (such as light, temperature, magnetic fields or ultrasounds) and biochemical (such as enzymes, antibodies, or DNA) stimuli. [5] From a different point of view, self-immolative molecules are covalent aggregates that, upon application of an external trigger, initiate a disassembly reaction, through a cascade of electronic elimination processes, leading ultimately to the release of its building blocks. [6] This chemical phenomenon is usually driven by a cooperative increase in entropy coupled with the irreversible formation of thermodynamically stable products. These molecules have been extensively used in several applications including the design of prodrugs, [7] sensors [8] and drug delivery systems. [9] Self-immolative processes can commonly be found for polysubstituted, electron-rich aromatic species containing an electron-donating substituent in conjugation (ortho or para) with a suitable leaving group located in a benzylic position. [10] In classical self-immolative linkers a single activation event leads to the release of a single group. This release can be described as non-amplified. In contrast the evolution of this technology has resulted in recent years in the design of self-immolative systems in which a single activation event leads to the delivery of multiple groups. This has been described as amplified release. [11] Scheme 1. (a) Schematic representation of the prepared gated nanoparticles S1, (b) synthesis of self-immolative molecular gate 1 and the cascade electronic eliminatio...

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Four types of calcined MCM-41 silica nanoparticles, loaded with dyes and capped with different gating ensembles are prepared and characterized. N1 and N2 nanoparticles are loaded with rhodamine 6G and capped with bulky poly(ethylene glycol) derivatives bearing ester groups ( 1 and 2 ). N3-N4 nanoparticles are loaded with sulforhodamine B and capped with self-immolative derivatives bearing ester moieties. In the absence of esterase enzyme negligible cargo release from N1, N3 and N4 nanoparticles is observed whereas a remarkable release for N2 is obtained most likely due to the formation of an irregular coating on the outer surface of the nanoparticles. In contrast, a marked delivery is found in N1, N3 , and N4 in the presence of esterase enzyme. The delivery rate is related to the hydrophilic/hydrophobic character of the coating shell. The use of hydrophilic poly(ethylene glycol) derivatives as gating ensembles on N1 and N2 enables an easy access of esterase to the ester moieties with subsequent fast cargo release. On the other hand, the presence of a hydrophobic monolayer on N3 and N4 partially hinders esterase enzyme access to the ester groups and the rate of cargo release was decreased.