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Lidocaine’s (Lido) low water solubility and negligible tissue uptake limit its bioavailability when applied to the skin. Nanoparticulate systems would help address these issues; therefore, lidocaine inclusion complexes with mesoporous silica nanoparticles (MSNs) were prepared and the effect of MCM41 surface functionalization with positively charged amino-propyl groups on the molecule properties studied. It is expected that positively charged nanoparticles can improve lidocaine permeation into the skin. The complexes were prepared in different lidocaine/MSNs ratios (3/1, 2/1, 1/1) and characterized by X-ray powder diffraction (XRD), dynamic light scattering (DLS) and differential scanning calorimetry (DSC). Fourier transform infrared (FTIR) spectroscopy provided detailed information regarding the molecular interaction of lidocaine with the inorganic surface. The optimized lidocaine-loaded MSNs (1/1) were used for in vitro release studies using dialysis membrane and ex vivo permeation studies by Franz diffusion cell.Higher drug release and skin permeation were observed for the functionalized complex over pure lidocaine and Lido/MCM41 which can be attributed to the electrostatic interaction between positively charged lido/MCM41-NH2 and negatively charged skin membrane cells. Therefore, MCM41-NH2 exhibited superiority over MCM41 and the free drug, suggesting the significance of functionalization in lidocaine dermal delivery.