Development of Au _<i>x</i> Cu _<i>y</i> Pd _<i>z</i> Nanocomposites as Therapeutic Agents: Enhancing Cancer Treatment through Autophagy Modulation and Immune-Associated Effects

The development of multimetallic nanoparticles for cancer treatment represents a significant advancement in the field of nanomedicine. We introduce a Cu-templated synthesis method to create Au_<i>x</i>Cu_<i>y</i>Pd_<i>z</i> hollow nanomicrostructures, wherein gold atoms stabilize copper (Cu) and facilitate the incorporation of palladium (Pd) through oxidation and coreduction processes. These ternary nanocomposites demonstrate enhanced cellular uptake via the copper transporter CTR1/2-mediated pathway and exhibit superior catalytic activity for the reaction of hydrogen peroxide to generate hydroxyl radicals. The presence of both Cu and Pd triggers significant autophagic responses, increases lipid peroxidation, and disturbs copper metabolism, as indicated by the increased expression of autophagy-related proteins and mitochondrial reactive oxygen species, ultimately leading to selective cancer cell death. The synergistic effects of these three metals not only increase autophagy but also promote the degradation of immune escapable proteins, including IDO1, PD-L1, and CD47. Based on the Cu/Pd element-induced biochemical stimulation, we conducted a proof-of-concept in vivo validation using a murine orthotopic bladder tumor model to demonstrate that Au-Cu-Pd ternary nanoparticles enhance autophagy and ferroptosis, thereby reversing the immunosuppressive tumor microenvironment by reducing immune escape proteins. These effects increased the infiltration of antitumor immune cells, with further enhancement from photothermal therapy at a low laser power density and sample dose. Our findings offer valuable insights into designing multimetallic nanoparticles through element chemistry for cancer therapy, highlighting their potential as effective modulators of autophagy.