Nanoparticles find intriguing applications in oral drug delivery since they present a large surface area for interactions with the gastrointestinal tract and can be modified in various ways to address the barriers associated with oral delivery. The size, shape and surface chemistry of nanoparticles can greatly impact cellular uptake and efficacy of the treatment. However, the interplay between particle size, shape and surface chemistry has not been well investigated especially for oral drug delivery. To this end, we prepared sphere-, rod- and disc-shaped nanoparticles and conjugated them with targeting ligands to study the influence of size, shape and surface chemistry on their uptake and transport across intestinal cells. A triple co-culture model of intestinal cells was utilized to more closely mimic the intestinal epithelium. Results demonstrated higher cellular uptake of rod-shaped nanoparticles in the co-culture compared to spheres regardless of the presence of active targeting moieties. Transport of nanorods across the intestinal co-culture was also significantly higher than spheres. The findings indicate that nanoparticle-mediated oral drug delivery can be potentially improved with departure from spherical shape which has been traditionally utilized for the design of nanoparticles. We believe that understanding the role of nanoparticle geometry in intestinal uptake and transport will bring forth a paradigm shift in nanoparticle engineering for oral delivery and non-spherical nanoparticles should be further investigated and considered for oral delivery of therapeutic drugs and diagnostic materials.

Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes, oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract, difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.

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Whether and to what extent solid lipid nanoparticles (SLNs) can be absorbed integrally via oral delivery should be clarified because it is the basis for elucidation of absorption mechanisms. To address this topic, the in vivo fate of SLNs as well as their interaction with biomembranes is investigated using water-quenching fluorescent probes that can signal structural variations of lipid-based nanocarriers. Live imaging indicates prolonged retention of SLNs in the stomach, whereas in the intestine, SLNs can be digested quickly. No translocation of intact SLNs to other organs or tissues can be observed. The in situ perfusion study shows bioadhesion of both SLNs and simulated mixed micelles (SMMs) to intestinal mucus, but no evidence of penetration of integral nanocarriers. Both SLNs and SMMs exhibit significant cellular uptake, but fail to penetrate cell monolayers. Confocal laser scanning microscopy reveals that nanocarriers mainly concentrate on the surface of the monolayers, and no evidence of penetration of intact vehicles can be obtained. The mucous layer acts as a barrier to the penetration of both SLNs and SMMs. Both bile salt-decoration and SMM formulation help to strengthen the interaction with biomembranes. It is concluded that evidence does not support absorption of intact SLNs via oral delivery.

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