Mesoporous silica nanoparticle-based substrates for cell directed delivery of Notch signalling modulators to control myoblast differentiation

Abstract

Biochemical cues are critical to control stem cell function and can be utilized to develop smart biomaterials for stem cell engineering. The challenge is to deliver these cues in a restricted manner with spatial and temporal control. Here we have developed bilayer films of mesoporous silica nanoparticles for delayed cellular delivery of Notch modulators to promote muscle stem cell differentiation. We demonstrate that drug-loaded particles are internalized from the particle-covered surface, which allows for direct delivery of the drug into the cell and a delayed and confined drug release. Substrates of particles loaded with γ-secretase-inhibitors, which block the Notch signalling pathway, promoted efficient differentiation of myoblasts. The particle substrates were fully biocompatible and did not interfere with the inherent differentiation process. We further demonstrate that impregnating commercially available, biocompatible polymer scaffolds with MSNs allows for a free standing substrate for cell directed drug delivery.

Internalization and fate of silica nanoparticles in C2C12 skeletal muscle cells: evidence of a beneficial effect on myoblast fusion

“…Below the toxic threshold, silica nanoparticles show potential development in biomedical research for bioimaging, diagnosis, drug delivery, and tissue engineering, including muscle regeneration therapy. 20,39,40 We have studied the internalization of silica NPs in myoblasts and characterized their biopersistence during in vitro cell differentiation, representing an excellent model for muscle regeneration. Interestingly, we showed that at low doses, NP uptake was able to increase the formation of myotubes by enhancing myoblast fusion.…”

“…For instance, the differentiation of myoblasts has been stimulated with the use of silica nanoparticles loaded with γ-secretase inhibitors, blocking the Notch signaling pathway. 20 Developments combining stem cells with nanoparticles provide an interesting strategy for cell therapy. 21 Because muscles are scarcely exposed to nanoparticles, little attention has been given to how silica nanoparticles interact with muscle cells, unlike exposed tissues.…”

“…21 In a recent report, silica nanoparticles loaded with Notch signaling modulators were used to induce efficient differentiation of myoblasts into myotubes. 20 C2C12 cells have been grown on a film of silica nanoparticles. After their cellular uptake, these nanoparticles delivered the Notch inhibitor, suggesting that a surface or a three-dimensional scaffold impregnated with nanoparticles can be used for celltargeted delivery.…”

Effect of electrolytes on proteins physisorption on ordered mesoporous silica materials

“…Several research groups have produced interesting advances in the use of silica materials for nanomedicine applications [29,[32][33][34]67,68]. Among several reviews the themed A c c e p t e d M a n u s c r i p t 10 features and applications are revised is worth citing [69].…”

“…Particularly, we can cite the huge contribution of Vallet-Regì et al [18,[26][27][28][29][30], and more recently the careful work of Linden et al [31][32][33]. OMS materials are able to adsorb, protect and release therapeutic proteins and peptides, being the aim the preparation of drug depot systems for sustained drug delivery or bone tissue engineering [17,18].…”