Modulating Anti-Inflammatory Macrophage Polarization and Regulatory T Cell Differentiation via Aminooxyacetic Acid-Loaded Hydrogel for Promoting Allogeneic Skin Transplantation

The long-term survival of allografts is primarily compromised by immune rejection, in which M1 macrophage-mediated tissue damage and effector T cell infiltration have been identified as major contributors. Current clinical immunosuppressive drugs face critical limitations, as they either fail to coordinately regulate these two immune cell populations or induce systemic infections and metabolic disorders. To address this challenge, we developed an aminooxyacetic acid (AOAA)-loaded hydrogel delivery system (AOAA-Gel) based on covalently cross-linked oxidized sodium alginate/carboxymethyl chitosan (OSA/CMCS). This hydrogel enables localized and sustained AOAA release, while avoiding systemic toxicity. Mechanistically, AOAA-Gel coordinately modulates the M1/M2 macrophage ratio while expanding regulatory T cells at the graft site, resulting in effective suppression of both effector T cell infiltration and chronic rejection. In a murine allogeneic skin transplantation model, AOAA-Gel establishes an immunosuppressive microenvironment, significantly prolonging graft survival. These findings demonstrate a potentially safer therapeutic strategy for maintaining sustained allograft function through localized immunomodulation.