Hyaluronic acid–ornithine crosslinked hydrogel as a superior 3D culture platform for high-quality exosome production in advanced wound healing

• A novel HA-Orn hydrogel enables scalable 3D culture, significantly increasing exosome yield compared to conventional 2D cultures. • 3D-derived exosomes exhibit enhanced pro-regenerative functions, including stimulation of proliferation, migration, angiogenesis, and ECM remodeling. • In vivo, 3D-Exo accelerates wound closure and reduces inflammation, demonstrating robust therapeutic efficacy and safety. • Mechanistic insights reveal distinct miRNA profiles and activation of regenerative signaling pathways, highlighting translational potential for cell-free therapies.