Enhanced oral insulin delivery with charge-reversible lipid nanoparticles.

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Oral insulin has therapeutic advantages, as it can mimic the endogenous insulin pathway and relieve patients from daily self-injections. Among the many investigated oral insulin delivery systems, lipid nanoparticle (LNP)-based drug delivery systems are considered promising platforms for improving oral insulin absorption due to their unique in vivo properties and high design flexibility. However, challenges such as toxicity and low oral bioavailability persist. Dioleoylglycerophosphate-diethylenediamine (DOP-DEDA) is a pH-responsive and charge-reversible lipid for cytosolic cargo delivery. In this study, an insulin-encapsulated DOP-DEDA-based LNP (Ins-LNP) system was developed to achieve highly biocompatible and efficient oral insulin delivery. The Ins-LNPs exhibited a positive charge at gastrointestinal pH levels of 1.2 and 6.8, suggesting enhanced stability in the acidic stomach environment and facilitating efficient absorption in the small intestine. In addition, they are noncationic at a physiological pH level of 7.4, indicating low toxicity. PEGylated Ins-LNPs had a particle size of 125.4nm, a polydispersity index of 0.047, and an encapsulation efficiency of 57.2%. PEGylated Ins-LNPs maintained their particle characteristics for more than 2h in simulated gastrointestinal fluid containing digestive enzymes. They also retained 89%, 51%, and 44% of insulin for 60min in simulated gastrointestinal/physiological fluid at pH levels of 1.2, 6.8, and 7.4, respectively. Furthermore, in vivo studies using streptozocin-induced diabetic mice demonstrated a pronounced and sustained hypoglycemic effect following oral administration, characterized by a ∼40% reduction in blood glucose levels for over 10h, indicative of an optimal pharmacodynamic profile. This favorable pharmacodynamic profile may mitigate the risk of clinically relevant hypoglycemia, enhancing patient compliance and overall treatment outcomes. Consequently, this research presents a promising LNP system for oral insulin delivery.