Pomegranate-derived nanovesicles as therapeutic agents for acute pancreatitis in a murine model: anti-inflammatory, antioxidant, and endocrine-protective properties.

Aim: Acute pancreatitis (AP) is an inflammatory disorder of the pancreas lacking specific therapy and frequently complicated by oxidative stress (OS) and long-term endocrine dysfunction, including pancreatogenic diabetes. Pomegranate-derived nanovesicles (PgNVs) contain bioactive lipids, proteins, and metabolites responsible for many health benefits of pomegranate juice. This study evaluated whether prophylactic PgNVs administration could mitigate pancreatic injury, OS, systemic inflammation, and subsequent endocrine impairment in a murine model of severe L-arginine-induced AP. Methods: Male C57BL/6J mice were distributed to three groups: control, AP, and AP + PgNVs. A single subcutaneous dose of PgNVs (10 µg; ≈ 5 × 1010 particles) was administered 2 h before AP induction via intraperitoneal L-arginine. Animals were analyzed at 3, 7, 30, and 60 days post-induction. PgNVs were isolated using differential centrifugation, tangential-flow filtration, and size-exclusion chromatography. Results: PgNVs pretreatment preserved pancreatic architecture, reduced edema, amylase activity, and interleukin 6 (IL-6) levels in both tissue and plasma by limiting nuclear factor-κB-p65 phosphorylation. PgNVs restored redox balance by upregulating NQO1 [NAD(P)H quinone dehydrogenase 1], improving oxidized glutathione (GSSG)/reduced glutathione (GSH) and homocystine/homocysteine ratios, and maintaining PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) expression. PgNVs protected β-cell mass, enhanced insulin secretion, and normalized glucose tolerance after AP. Proteomic profiling revealed that PgNVs changed extracellular vesicle composition, lowering pro-inflammatory markers [fibronectin, dipeptidyl peptidase-4 (DPP4)] and restoring anti-inflammatory ITIH4 (inter-alpha-trypsin inhibitor protein heavy chain 4). Conclusion: PgNVs exert anti-inflammatory and antioxidant protection in experimental AP and preserve long-term endocrine function, highlighting their potential as a natural nanotherapeutic strategy to prevent pancreatic injury and post-pancreatitis diabetes.