A large-pore mesoporous Au@Pt@Rh trimetallic nanostructure with hyperthermia-enhanced enzyme-mimic activities for immunomodulation-improved tumor catalytic therapy

Catalytic therapy based on the nanozymes is an emerging strategy for tumor therapy. However, its therapeutic outcomes are considerably limited by many characters in tumor microenvironment (TME), such as hypoxia, immunosuppression, and insufficient endogenous hydrogen peroxide (H2O2) level. Herein, a new layer-by-layer trimetallic nanozyme (Au@Pt@Rh) with large mesopores is developed for immunoregulation enhanced tumor nanocatalytic therapy. Such outside-in porous Au@Pt@Rh nanozyme exhibits both intrinsic peroxidase (POD)- and catalase (CAT)-like activities under acidic TME, which can catalyze H2O2 into hydroxyl radicals (·OH) and oxygen (O2), respectively. Meanwhile, Au@Pt@Rh-enabled photothermal hyperthermia improves the POD- and CAT-mimic activities. With the assistance of homologous tumor cell membrane (CM), the TGF-β inhibitor (LY2157299, LY) is successfully loaded and retained in the large mesopores of Au@Pt@Rh-CM. LY-Au@Pt@Rh-CM nanocomposites can improve tumor immunosuppressive microenvironment through polarizing the macrophages from M2 to M1, and thus induce the regeneration of H2O2 to promote the catalytic activities. Both in vitro and in vivo results demonstrate that LY-Au@Pt@Rh-CM is able to effectively reprogram immunosuppressive TME, relief the tumor hypoxia, produce highly toxic ·OH, and therefore yield increased therapeutic efficiency upon laser irradiation of tumors. Therefore, this study provides a promising strategy for immunomodulatory enhanced tumor catalytic therapy based on polymetallic nanozymes.