A Dual-Functional Injectable Polysaccharide Hydrogel Incorporating Oxygen-Carrying Nanoemulsion and VEGF for Enhancing Islet Survival and Glycemic Control in Diabetic Mice

Abstract Type 1 diabetes (T1D) arises from autoimmune destruction of pancreatic β-cells, leading to lifelong dependence on exogenous insulin. Clinical islet transplantation offers a potential cure by restoring endogenous insulin secretion; however, its success is critically limited by poor post-transplant vascularization and oxygen deprivation, which cause over 70% of transplanted islets to undergo early necrosis or apoptosis. To address these challenges, we developed an injectable, biodegradable dual-functional hydrogel composed of oxidized hyaluronic acid (OHA) and carboxymethyl chitosan (CMC). This polysaccharide-based platform co-delivers vascular endothelial growth factor (VEGF) and an oxygen-carrying perfluorotributylamine (PFTBA) nanoemulsion, enabling simultaneous enhancement of angiogenesis and oxygenation within the graft microenvironment. The OHA/CMC hydrogel exhibited excellent biocompatibility, tunable gelation, and sustained release of both oxygen and VEGF. In vitro, hydrogel-encapsulated islets demonstrated markedly improved resilience under hypoxic stress, exhibiting an 8.6-fold increase in viability after 6 hours and a 4.0-fold enhancement in glucose-stimulated insulin secretion (GSIS) after 48 hours under 0% O2. In streptozotocin-induced diabetic mice, transplantation with the OHA/CMC–PFTBA–VEGF hydrogel enabled rapid restoration of endogenous insulin secretion, reversal of severe hyperglycemia, prolonged graft function, and enhanced neovascularization at the implant site. Collectively, this multifunctional hydrogel represents a promising and translatable therapeutic platform for improving islet transplantation outcomes in T1D and potentially advancing broader applications in regenerative medicine and complex tissue engineering.