From Nature to Nanoparticles: Advancing Oral Delivery Through Intestinal Permeation Enhancement

Oral delivery is the most patient-friendly mode of drug administration. Unfortunately, it is not possible for most protein and other macromolecular drugs because the gastrointestinal tract is not permeable to undigested large molecules. Although many chemical permeation enhancers have been identified that improve the intestinal absorption of biologics, they often cause cytotoxicity or damage the intestinal mucosa. In this talk, I will describe highlights from our lab’s work developing nature-inspired permeation enhancers. These include pelargonidin, a red pigment found in strawberries, that we identified in a screen of over 100 fruits, vegetables, herbs, and fungi. Separately, while preparing fruits for those experiments, we noticed that fruit blends with varying colloidal properties differentially caused permeation enhancement in cell culture. This stray observation led to the discovery of small anionic silica nanoparticles (~20-50 nm) that induce intestinal permeability by binding integrin receptors on the surface of intestinal epithelial cells. Both enhancer systems led to potent oral delivery in mice (30-100% insulin bioactivity) without discernable inflammation or toxicity. These findings underscore the potential of combining engineering and natural product approaches to solve fundamental challenges in drug delivery, opening new avenues for patient-friendly oral administration of biologics.