The surface chemistry and size of nanoparticles can greatly impact their interaction with biological pathways and alter efficacy. However, the interplay between surface modification and particle size has not been well investigated especially for oral delivery. It is necessary to maximize the bioavailability of loading therapeutics. Here, we prepared different sized mesoporous silica nanoparticles (100-500 nm) and conjugated them with polyethylenimine-coated carbon dots (PCD) for effective transepithelial absorption. The nanoparticles were also coated with polyethylene glycol (PEG) polymers for improved mucus permeability. These mesoporous silica nanoparticles conjugated to PCD and coated in PEG (MSN@PCD@PEG) were used to study the influence of particle size and surface chemistry on transepithelial transport and bioavailability. Results demonstrated that the MSN@PCD@PEG with a diameter 250 nm had the highest transepithelial transport and oral bioavailability compared to other formulations. Drug release, endocytosis pathways, transepithelial transport and degradation of these different nanocarriers were systematically studied in order to investigate effects of size variety. The findings indicated that nanoparticle-based oral drug delivery can be potentially improved by adjusting physicochemical properties. We believe that understanding the importance of surface chemistry and particle size in the oral delivery will improve nanoparticle engineering and oral application. (C) 2017 Elsevier Inc. All rights reserved.