Abstract
Natural nanodelivery systems are highly desirable owing to their biocompatibility and biodegradability. However, these delivery systems face challenges from potential degradation in the harsh gastrointestinal environment and limitations imposed by the intestinal mucus barrier, reducing their oral delivery efficacy. Here, gastrointestinal stable and mucus-permeable pea albumin nanomicelles (PANs) with a small particle size (36.42 nm) are successfully fabricated via pre-enzymatic hydrolysis of pea albumin isolate (PAI) using trypsin. Capsaicin (CAP) is used as a hydrophobic drug model and loaded in PAN with a loading capacity of 20.02 μg/mg. PAN exhibits superior intestinal stability, with a 40% higher CAP retention compared to PAI in simulated intestinal digestion. Moreover, PAN displays unrestricted movement in intestinal mucus and can effectively penetrate it, since it increases the mucus permeability of CAP by 2.5 times, indicating an excellent ability to overcome the mucus barrier. Additionally, PAN enhances the cellular uptake and transcellular transport of CAP with endoplasmic reticulum/Golgi and Golgi/plasma membrane pathways involved in the transcytosis and exocytosis. This study suggests that partially enzymatically formed PAN may be a promising oral drug delivery system, effectively overcoming the harsh gastrointestinal environment and mucus barrier to improve intestinal absorption and bioavailability of hydrophobic bioactive substances.