Zwitterionic polydopamine modified nanoparticles as an efficient nanoplatform to overcome both the mucus and epithelial barriers

Nanoparticles have opened a new perspective for oral drug delivery. However, nanoparticle transport is strongly hindered by mucus and epithelial barriers before they can enter the systemic circulation. We here establish a Poly(lactic-co-glycolic acid) (PLGA)-based nanoparticle platform with various surface modifications: Poly(ethylene glycol) (PEG), Poly(vinyl alcohol) (PVA) with different molecular weights and degrees of hydrolysis, Pluronic F127 (F127), and Polydopamine (PDA). We then systematically evaluate the mucus penetrability and cellular uptake of these different nanoparticles. Results demonstrate that both the unmodified PLGA and PVA-modified PLGA nanoparticles showed poor mucus penetrating ability as a consequence of strong interactions with the mucin fibers. Moreover, although the PLGA-PEG and PLGA-F127 nanoparticles exhibit relatively satisfactory mucus penetrability, they are not readily taken up by epithelial cells. In contrast, PDA-modified PLGA nanoparticles not only facilitate rapid mucus penetration, but also enhance the cellular uptake both in vitro and in vivo, thanks to the zwitterionic surface property of PLGA-PDA nanoparticles. This study therefore demonstrates the usefulness of zwitterionic modification by PDA polymer in allowing nanocarriers to sequentially penetrate the mucus and epithelial barriers, with significant potential for further application to oral drug delivery.