Erythrocyte-Derived Bioactive Nanovesicles Reverse the Immunosuppressive Function of Adenosine for Tumor Photoimmunotherapy

Adenosine has garnered significant attention as a potential target for overcoming tumor immune evasion. It exacerbates the immunosuppressive tumor microenvironment (TME) by incapacitating various protective immune cells. However, inhibitors targeting adenosine receptors are limited by incomplete blockade effects and off-target toxicity, necessitating the exploration of more effective strategies. Inspired by the native biologic function of adenosine deaminase (ADA) in hydrolyzing adenosine, a bioactive catalytic nanovesicle (ENV@FeS) is designed to reverse adenosine immunosuppressive function. The nanovesicle is constructed through the serial extrusion of erythrocytes abundant with ADA, coupled with the synthesis of FeS complex in situ using Fe2+ in erythrocytes via H2S gas introduction. Notably, the bioactive nanovesicles not only promote tumor targeting and induce immunogenic cell death by the FeS-induced photothermal effect, but also hinder the adenosine pathway by metabolizing adenosine into immunopotentiator inosine, further boosting antitumor immunity. In vivo, ENV@FeS efficiently increases the infiltration of cytotoxic T lymphocytes and M1 macrophages while reducing the production of regulatory T cells and myeloid-derived suppressor cells, resulting in significant inhibition of tumor growth. Together, the biomimetic nanovesicle-mediated adenosine metabolic regulation, in synergy with photothermal therapy, leads to a marked improvement in the immunogenic TME and enhances the therapeutic efficacy of photoimmunotherapy. A bioactive biomimetic nanovesicle, co-containing the natural adenosine deaminase and photothermal agent FeS, is innovatively designed and fabricated based on erythrocytes. The nanovesicle effectively reverses adenosine's immunosuppressive function, and in synergy with photothermal therapy, leads to a significant improvement in the immunogenic tumor microenvironment and enhances the therapeutic efficacy of photoimmunotherapy. image