Critical material designs for mucus- and mucosa-penetrating oral insulin nanoparticle development

Subcutaneous and pulmonary insulin is associated with medical and pharmaceutical complications. Oral insulin mimics physiological glucose regulation with reduced hypoglycemia and coma risks. Nanoparticles are advocated as oral insulin carrier to overcome intestinal absorption barrier. Their insulin bioavailability and blood glucose lowering performances are hampered by inefficient mucus and mucosa transport of nanoparticles. This review discusses critical materials used in oral insulin nanoparticle design to address mucus and mucosa penetrating hurdles. It highlights intestinal receptor targeting, biomimetic virus mimicking, particulate surface charge switching, coat-core detachment, and combination approaches developed through material sciences. Mucus penetration favors particles with hydrophilic/amphiphilic surfaces with no net charges. Mucosa penetration shows a preponderance for hydrophobic or positively charged surfaces with intestinal receptor binding affinity. Materials with switchable physicochemical properties along with mucus-mucosa transit require research exploration, with consideration of their influences on endocytosis, lysosomal escape, exocytosis, and intestinal receptor upregulation.