Enhanced intestinal mucosal retention via polypseudorotaxane-microsheets for oral drug delivery

Oral delivery is the most acceptable administration route. However, the intestinal mucus layer remains the major barrier that prevents intact drug carriers from contacting epithelial cells and entering the systemic circulation. The geometry of oral nano/micro-carriers plays a key role in affecting the mucus permeation and transmembrane transport so as to prolong intestinal residence and enhance epithelium traversal. Here, polypseudorotaxane microsheets (PPRMs) with different side lengths and thicknesses were fabricated via host-guest inclusion between β-cyclodextrin and short-chain diblock surfactants. PPRMs have good structural stability in simulated gastrointestinal fluids and intestinal mucus conditions. PPRMs exhibited typical controlled release characteristics in simulated mucus layer. Among the four PPRMs, OP10-PPRM shows superior mucoadhesive capability toward the intestinal mucus layer due to their favorable wettability and small side length. Three types of PPRMs enhance the penetration depth into intestinal mucus, and OP10-PPRM also prolongs the intestinal retention time in vivo. The payloads in PPRMs could either be released after dissociation or internalized into epithelial cells with intact form. Overall, PPRMs as drug nano/micro-carriers can effectively enhance intestinal mucosal retention and overcome oral drug delivery barrier owing to their geometrical advantages.