The present work reports the effect of polysaccharides (chitosan and sodium alginate) on silica nanoparticles (SiNP) for hydrophilic molecules delivery taking insulin as model drug. The influence of tetraethyl orthosilicate (TEOS) and homogenization speed on SiNP properties was assessed by a 22 factorial design achieving as optimal parameters: 0.43 mol/L of TEOS and homogenization speed of 5000 rpm. SiNP mean particle size (Z-Ave) was of 256.6 nm and polydispersity index (PI) of 0.218. SiNP coated with chitosan (SiNP-CH) or sodium alginate (SiNP-SA) increased insulin association efficacy; reaching 84.6% (SiNP-SA) and 90.8% (SiNP-CH). However, coated SiNP released 50%–60% of the peptide during the first 45 min at acidic environment, while uncoated SiNP only released 30%. Similar results were obtained at pH 6.8. The low Akaike’s (AIC) values indicated that drug release followed Peppas model for SiNP-SA and second order for uncoated SiNP and SiNP-CH (pH 2.0). At pH 6.8, the best fitting was Boltzmann for Ins-SiNP. However, SiNP-CH and SiNP-SA showed a first-order behavior. Cytotoxicity of nanoparticles, assessed in Caco-2 and HepG2 cells, showed that 100 to 500 µg/mL SiNP-CH and SiNP-SA slightly decreased cell viability, comparing with SiNP. In conclusion, coating SiNP with selected polysaccharides influenced the nanoparticles physicochemical properties, the insulin release, and the effect of these nanoparticles on cell viability.