Bilayer-functionalized mesoporous silica nanoparticles for overcoming multiple barriers of mucus clearance, intestinal epithelium and P-glycoprotein efflux

[Display omitted] •Bilayer-functionalized mesoporous silica nanoparticles were designed via layer-to-layer assembly for overcoming multiple gastrointestinal barriers.•Sulfobetaine coating layer could shield particle-mucin interactions and improve mucus penetration.•D-α-tocopheryl polyethylene glycol succinate modified inner layer enhanced transepithelial absorption and suppressed p-glycoprotein efflux of puerarin.•This dual strategy significantly improved oral bioavailability and in vivo anti-inflammatory efficacy of puerarin. Mucus clearance, epithelium mucosal barrier and P-glycoprotein (P-gp) efflux are the main gastrointestinal barriers that limit the oral delivery of nanoparticles. Inspired by tunable particles surface properties-dependent trans-mucus and trans-mucosal abilities, novel bilayer-functionalized mesoporous silica nanoparticles (MSN) containing D-α-tocopheryl polyethylene glycol succinate (TPGS) and sulfobetaine 12 (SB12) were designed by layer-to-layer assembly. The amino-grafted MSN (MSN-NH2) was firstly functionalized with TPGS as hydrophobic layer (MSN-TPGS), and then SB12 was self-assembled on the hydrophobic surface of MSN-TPGS to generate a neutral and hydrophilic MSN (MSN-TPGS@SB12). Compared with MSN-NH2, MSN-TPGS, and MSN-TPGS@P123, the MSN-TPGS@SB12 possessed “one stone three birds” functions that enhanced mucus penetration, increased trans-mucosal absorption, as well as suppressed P-gp efflux. The pharmacokinetics study demonstrated that the MSN-TPGS@SB12 loading puerarin (MSN-TPGS@SB12-PUE) exhibited much higher bioavailability compared to other PUE-loaded formulations. Furthermore, the MSN-TPGS@SB12-PUE could significantly enhance the anti-inflammatory efficacy of PUE in vitro and in vivo. In summary, bilayer-functionalized MSN-TPGS@SB12 is a promising vehicle for overcoming the multiple gastrointestinal barriers (mucus clearance, intestinal epithelium barrier and P-gp efflux). Meanwhile, this study also provides a better understanding of the importance of tunable surface property of MSN on oral delivery of drugs.