*4.3. Enzyme-Responsive Gatekeepers*

MSN drug release can also be modulated by the enzymatic cleavages of ester, peptide, urea, and oxamide bonds decorated on theMSN surface. Several enzymes such as esterase, protease, galactosidase, amylase, lipase, etc. have been exploited for enzyme responsive controlled drug release [166]. In this regard, Patel et al. have introduced ester bonds between MSN and the adamantine capping moiety, to employ the enzymatic role of porcine liver esterase for the controlled release of cargos [167]. Mondragón et al. have exploited protease cleavable ε-poly-l-lysine moiety to seal the camptothecin encapsulated MSN and reported the reduced viability of human cervix epitheloid carcinoma cells upon treatment of that nanosystem [168]. They have also reported some enzyme-responsive hydrolyzed starch products as saccharides to be used for controlled drug release [169]. There are various other protease-responsive moieties that have been used to cap the MSN pores and improve the drug release, e.g., protease-responsive biotin-avidin [170], arginine-rich protamine proteins [171], matrix metalloproteinase (MMP) degradable gelatin [172], avidin with MMP9-sensitive peptide linker (RSWMGLP) [173], poly (ethylene glycol) diacrylate moiety with protease-sensitive peptide linker (CGPQGIWGQGCR) [174]. Furthermore, cyclodextrin gatekeepers and HRP-polymer nanocapsules have also been employed on the MSN surface for enzyme-responsive drug release [175,176].

## *4.4. Magnetic Responsive Delivery System*

One of the e ffective ways to exploit external stimuli is to exert the magnetic field on MSN, either to have magnetic guidance by applying the permanent magnetic field, or to increase the temperature by applying an alternating magnetic (AM) field [177,178]. In this regards, iron oxide has been widely exploited as the required magnetic component. There are mainly two ways that have been used to conjugate iron oxide with MSN, either using iron oxide core coated with mesoporous silica or MSN capped with iron oxide nanoparticles [179,180]. The most employed strategy consists on encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) of ca. 5–10 nm within the MSN network during their synthesis [181,182]. These SPIONs are able to convert the magnetic energy into heat and can increase the local temperature of the system upon application of the AM field. If the surface of MSN has already been coated with temperature responsive moieties acting as gatekeepers, e.g., poly (N-isopropylacrylamide), pore opening and drug release from MSN can be triggered by applying an AM field [183]. Taken together, upon application of an AM field, SPIONs encapsulated in MSN can increase the local temperature up to a certain point, to change the conformation of the temperature responsive gatekeepers and open the pore entrances to release the anti-cancer drugs e fficiently without having any premature leakage. There are several reports showing the controlled release of anti-cancer therapeutics by applying a magnetic stimulus [180,184,185]. Moreover, there are a few FDA-approved SPIONs for using as imaging agents and EU-approved iron oxide nanoparticles to use in glioblastoma therapy; these can be further exploited in magnetic responsive drug delivery [20].

Another strategy for the design of the magnetic responsive delivery system consists of the functionalization of drug-loaded MSN with a single DNA strand and then mixing this with SPIONs functionalized with the complementary DNA strand, to allow DNA hybridization that can act as a capping agen<sup>t</sup> [186]. The reason behind selecting the DNA sequence is its melting temperature of 47 ◦C. Thus, upon application of an AM field, SPIONs encapsulated into the MSN network can increase the local temperature that subsequently trigger the double-stranded DNA melting and open the pores of MSN to release the drug. Interestingly, when the magnetic field is switched o ff, the DNA hybridization occurs again, thus closing the pores and stopping the drug release. This mechanism smartly provides the chance of exploiting the on-o ff drug release mechanism.
