Tea-derived extracellular vesicles-mediated PDRN delivery activates cAMP-HIF-1α to restore intestinal homeostasis in inflammatory bowel disease

The clinical translation of polydeoxyribonucleotide (PDRN), a bioactive agent with anti-inflammatory and tissue-repair properties, is hindered by significant oral delivery barriers. This study utilizes inflammatory bowel disease (IBD) as a disease model, which is characterized by a vicious cycle of excessive oxidative stress, immunological homeostasis imbalance and intestinal flora dysbiosis in the colon. Leveraging the targeted delivery advantages of tea-derived extracellular vesicles (EV), we have developed them as nanocarriers to overcome the oral delivery challenges of PDRN (PDRN-EV). PDRN-EV exhibits excellent structural stability under simulated gastrointestinal conditions. In vitro studies demonstrated that PDRN-EV exerts therapeutic effects via dual synergistic mechanisms of anti-oxidative stress and immunomodulation. Furthermore, the anionic surface properties of PDRN-EV promote selective accumulation at inflammatory sites, while surface-exposed monogalactosyldiacylglycerol and digalactosyldiacylglycerol (MGDG/DGMG) galactolipids mediate the specific targeting phagocytosis of macrophages. In vivo experiments conducted in a dextran sulfate sodium (DSS)-induced colitis model demonstrated that orally-administered PDRN-EV significantly alleviates adverse characteristics such as pro-inflammatory responses and impaired intestinal barrier function. The underlying mechanism involves driving macrophage M2 polarization through activation of the cAMP/HIF-1α signaling pathway, promoting DNA replication, and restoring microbiota equilibrium. This work establishes a novel oral nanotherapeutic strategy for IBD that circumvents gastrointestinal degradation and off-target effects. The development of an orally-administered nanocomposite based on polydeoxyribonucleotide loaded tea-derived extracellular vesicles (PDRN-EV) is described for inflammatory bowel disease (IBD) therapy, which ameliorates the pro-inflammatory responses and restores intestinal barrier functions through synchronous ROS-scavenging, immunomodulation, and modulation of gut microbiota. This study bridges the critical gap between nucleic acid pharmacology and clinical translation. • Tea-derived extracellular vesicle (EV)-based oral PDRN delivery system overcoming gastrointestinal degradation barriers. • EV carriers demonstrate bioactivities synergizing with PDRN DSS-induced colitis. • EV surface galactolipids enable receptor-mediated macrophage targeting. • PDRN-EV activates cAMP/HIF-1α axis to drive M2 polarization • A multifunctional integrated nanoplatform for nucleic acid drug delivery.