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It was the aim of this study to combine two strategies – namely the virus-mimicking strategy and the surface PEGylation strategy – in order to generate highly mucus permeating nanocarriers for oral insulin delivery.Chondroitin sulphate was covalently conjugated with poly(ethylene glycol) 5 kDa at different degree of modification and with the functionalized polymers NPs were formulated via complexation with chitosan. NPs were characterized by particle size, zeta potential, surface hydrophilicity and permeation ability in porcine mucus and on excised mucosa.The NPs presented a size between 510 and 670 nm and a zeta potential between −1 and −5 mV when dispersed in simulated intestinal fluid. The mucus permeation test revealed a correlation between the NPs hydrophilicity and their ability to move through mucus. A 5-fold higher amount of NPs with the higher degree of PEGylation could permeate through fresh mucus compared to non-PEGylated NPs. Moreover, highly PEGylated NPs showed a 3.7-fold greater ability to be retained in intestinal mucosa against buffer flow compared to unmodified NPs. Finally, insulin was incorporated with a payload of 2.18% and the release profile showed a 65% release within 4 h.Results of this study provide strong evidence for the potential of combining different surface modification strategies in order to improve the mucus permeating properties of NPs for oral peptide delivery.