Artificial Regulatory T Cells Orchestrate Phase-Spanning Regeneration in Refractory Tissue Injuries

Regulatory T cells (Tregs) possess potent multiphasic reparative capacity; however, their application is limited by ethical and regulatory challenges associated with live cell therapies. Treg-derived exosomes (TExo) exhibit low immunogenicity while enriching regenerative signaling relative to parental Tregs. Current exosome carriers place greater emphasis on sustained release than on factors affecting vesicle stability, such as nonspecific interactions and confinement effects. Inspired by the multivesicular body (MVB), we engineered artificial Tregs (ATregs) with an MVB-like architecture that integrates vesicle protection with sustained release through a reconstructed storage microenvironment. This design enables phase-aligned TExo release and extends functional activity by more than an order of magnitude compared with free TExo. ATregs sequentially coordinate the suppression of inflammation, enhancement of angiogenesis, and stimulation of skin appendage regeneration. In diabetic wounds and deep second-degree burn models, which represent intrinsic repair dysfunction and severe structural tissue loss, ATregs markedly accelerate healing and outperform conventional strategies across murine and porcine models. These findings overcome the key limitations of exosome therapies and open a new avenue for next-generation regenerative therapeutics.