Loading Nanoceria Improves Extracellular Vesicle Membrane Integrity and Therapy to Wounds in Aged Mice

Wound healing is a programmed process through which tissue restores its integrity after an injury. Advancing age is a risk factor for delayed cutaneous wound healing; however, ideal therapeutic approaches for aged wound have not been developed yet. By dissecting the harsh microenvironment of aged wound, we propose an integrated chemical and biological strategy to mitigate two main hostile factors including oxidative stress and ischemia. Mesenchymal stem cell-derived extracellular vesicles (EVs) are a rising star in regenerative medicine due to their powerful facilitation in tissue repair and regeneration. However, the fragile lipid membrane limits their function under the oxidative stress microenvironment. Nanoceria is an antioxidative nanozyme; here, we reveal that nanoceria-loaded EVs derived from mesenchymal stem cells facilitate cutaneous wound healing in aged mice. DG-CeO₂ was prepared via coating CeO₂ covalently with d-glucose to promote their cellular endocytosis. DG-CeO₂ was packaged into EVs under optimized hypoxic conditions (DG-CeO₂ EVs^Hyp). We further demonstrated that DG-CeO₂ EVs^Hyp had favorable biocompatibility and antioxidative and proangiogenic effects during the cutaneous wound healing in both young and aged mice. Further evidence revealed that DG-CeO₂ EVs^Hyp-transferred miR-92a-3p/125b-5p and their targets associated with aging degeneration may be the potential mechanisms. Collectively, these findings highlight that nanoceria-loaded EVs released by engineered stem cells may represent a potential therapeutic approach for tissue regeneration in aged population.