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Nanoparticles (NP) only different in mucoadhesivity are compared for impact on drug oral bioavailability. Two polymeric NP types based on quaternary ammonium-chitosan (NP QA-Ch) and S-protected thiolated derivative thereof (NP QA-Ch-S-pro), respectively, containing the macromolecular drug model, FD4, were prepared by crosslinking each polymer with reduced MW hyaluronic acid. The structure of basic polymers was determined by H1NMR analysis. NP were similar in size (371±38 vs. 376±82nm); polydispersity index (0.39±0.08 vs. 0.41±0.10); zeta potential (13.4±0.9 vs. 11.9±1.2mV); reversible interactions with drug (bound drug, 67 vs. 66%); encapsulation efficiency (23±5 vs. 23±8%); release properties (15% released in 15h in both cases); and apparent permeation across excised rat intestine (Papp, 8.8±0.8 vs. 10±1cm/s). Then the differences in NP transport ratio through mucus (TR, 0.75 vs. 0.37) and adhesion to excised rat intestinal mucosa (adsorbed fraction, 23±3 vs. 45±2%) were ascribed to higher mucoadhesivity of NP QA-Ch-S-pro compared to NP QA-Ch. This directly influenced drug oral bioavailability in rats (Tmax, 1 vs. 2h; AUC, 1.7±0.3 vs. 2.9±0.4μg/mL min, for NP QA-Ch and NP QA-Ch-S-pro, respectively). Mucoadhesivity increases drug bioavailability by retaining NP at its absorption site and opposing its transit down the GI tract. Data on drug accumulation in rat liver allows the assertion that NP is absorbed by transcytosis across intestinal epithelium and transported from blood into liver by Kuppfer cells.