Oral gene delivery platform based on glycol chitosan-PEG-lactoferrin conjugate

Oral gene delivery offers an alternative to parenteral administration for managing chronic metabolic disorders such as type 2 diabetes mellitus (T2D). However, its development has been limited by enzymatic degradation within the gastrointestinal tract and inefficient intestinal absorption. To overcome these obstacles, we developed a non-viral oral gene delivery system based on a glycol chitosan-maleimide-polyethylene glycol-N-hydroxysuccinimide ester-lactoferrin (GPL) platform. We then applied this platform to deliver fibroblast growth factor 21 (FGF21), a key regulator of glucose and lipid metabolism, through lactoferrin receptor-mediated transcytosis. Oral administration of the GPL/FGF21 polyplex achieved circulating FGF21 levels comparable to intraperitoneal injection. This resulted in a ∼ 37 % reduction in fasting glucose and a ∼ 47 % improvement in insulin sensitivity in high-fat diet (HFD)-induced T2D mice, accompanied by systemic FGF21 protein expression. Collectively, this GPL-based oral gene delivery system represents a promising gene therapeutic strategy with broad applicability for metabolic diseases.