# Therapeutic Potential of Polymer-Coated Mesoporous Silica Nanoparticles
## 7 Polymer Coated MSNs for Gene Delivery  
Cationic particles are mostly investigated for gene delivery due to nucleic acids being highly negatively charged, thus allowing complexation and, ultimately, better transfection efficiency. PEI is therefore, the most employed and efficient in vitro gene transfection vector, but due to its cytotoxicity, it is not suitable for therapeutic applications. Nevertheless, when derivatized, or used as a construct in drug delivery system design, the cytotoxicity of plain PEI can be significantly suppressed [40]. Therefore, MSNs \(\sim\)100 nm in size coated with PEI and PEG polymers were utilized by [PERSON] et al. to deliver siRNA to HER2+ breast cancer cells. PEI coating was performed followed by cross-linking (by bio-reducible cross linker), to promote the endosomal escape of particles via the alleged proton sponge effect, whereas PEG coating protected the siRNA from degradation and avoid aggregation and adverse immune response from the cationic nanoparticles. Trastuzumab was used as a ligand for the selective uptake of nanoparticles by cancerous cells. These nano-constructs were selectively taken up by HER2+ cells via the antibody-receptor interaction and successfully silenced HER2 expression, as evident from in vitro and in vivo experiments [62]. Furthermore, similar nanoparticles were used to deliver Polo-like kinase 1 siRNA (PLK1) for the treatment of triple negative breast cancer. The treatment was able to bring down the onset of death in mice and improved the overall survival in a TNBC mice model. The authors also claimed that these modified MSNs are capable to scavenge intracellular ROS and modulate NOX4 activity, which results in the inhibition of cellular invasion and migration in breast cancer cells in vitro [71]. PEI coated phosphonated MSNs were also evaluated for the delivery of plasmid DNA by [PERSON] et al. The coating was performed by electrostatic complexation between cationic PEI on anionic phosphonate modified MSNs, which also lead to a reduction in PEI toxicity. The transfection of particles was tested on Neuro-2A cells and found that transfection efficiency of MSN-PEI modified with 10 and 25 kDa respectively at C/P of 0.5 was significantly higher than PEI 10 and 25 kDa polymer. The authors also demonstrated that the loading of chloroquine, a lysosomeotropic compound, does not always enhance the transfection efficiency [63]. PEI is not only useful for enhancing the transfection efficiency, but also for complexing/loading the negatively charged nucleic acids. Therefore, in one of our own studies, we functionalized MSNs with surface-hyperbranched PEI for the efficient loading of siRNA, which was covalently attached to the MSNs tethered via redox-cleavable linkers. The hyperbranched structure of surface-grown PEI provided a high surface concentration of attachment sites for the siRNA, yielding loading degrees of 120 mg\(\cdot\)g\({}^{-1}\). To ensure efficient cellular uptake, a second layer of short (low MW) PEI was attached to the surface of MSNs, yielding an overall positive surface charge. Triggered by the intracellular redoxconditions, the siRNA was sustainably released inside the cells over a period of several days. These hybrid nanocarriers prospectively allow for more efficient and long-term siRNA delivery, suitable also for therapeutic gene silencing in RNA interference (RNAi) therapy [72] while yielding an overall positive net surface charge for efficient intracellular uptake. In another study, MSNs loaded with lanthanide-doped upconversion nanoparticles (UCNPs) covered with PEG or PEG-folic acid was employed for effective delivery of siRNA. PEG was coated via a photodexvable linker to introduce a photoresponsive characteristic, which controls the release of loaded siRNA. The irradiation of 980 nm light cleaves the linker and eradicates PEG from the MSN surface to release siRNA at the target site.