Methacrylamide Hyaluronic Acid/Tannic Acid Hydrogel Loaded with Tomato and HEK 293 Cell-Derived Exosomes for Diabetic Wound Repair

The repair of diabetic wounds is constrained by persistent inflammatory responses, excessive reactive oxygen species, and compromised angiogenesis, necessitating novel therapeutic strategies to modulate the immune microenvironment and promote tissue repair. Exosomes isolated from human embryonic kidney 293 cells (293-Exo) possess a high content of bioactive cargo and have been shown to markedly enhance the repair of diabetic wounds. In addition, extracellular vesicles originating from plants are increasingly recognized as a promising new class of therapeutic agents. Tomato fruit juice-derived exosomes (TM-Exo) can significantly reduce oxidative stress, regulate macrophage polarization, and protect islet function, holding significant promise for treating diabetic wounds. Nevertheless, topical administration of exosomes at wound sites is hampered by intrinsic instability and rapid clearance, which markedly constrains their translational and clinical potential. This study developed a multifunctional bioactive dressing (TE/293E-Gel) based on a photo-cross-linked methacrylamide hyaluronic acid/tannic acid (HAMA/TA) hydrogel, coencapsulating 293-Exo and TM-Exo to synergistically promote diabetic wound healing. This hydrogel possesses excellent mechanical properties, tissue adhesion, controllable degradability, and good biocompatibility. This bioactive agent vigorously enhances cell motility and angiogenic processes, repolarizes macrophages from an inflammatory M1 profile toward a reparative M2 program, and concurrently affords antioxidative and anti-inflammatory benefits. In conclusion, the designed photo-cross-linked hydrogel encapsulating exosomes from two distinct sources significantly accelerates diabetic wound repair through multiple mechanisms, demonstrating significant translational potential.