Spatial Isolation of Single Copper(I) Sites for Cascade Enzyme-Like Catalysis and Simultaneous Ferroptosis/Cuproptosis Boosted Immunotherapy

Abstract

Nanozyme-based immunogenic cell death (ICD) inducers that effectively induce a strong immune response via enzyme-like process have attracted great attention, but how to ensure controllable active sites and maximize site utilization remains a problem. Here, we report a structurally well-defined and highly functional single-site copper(I) nanomodulators termed CuNTD, constructed by precisely anchoring atomically dispersed self-assembly S-Cu(I)-S sites onto a two-dimensional Ti₃C₂ surface. Leveraging Cu⁺ with a higher catalytic efficiency than Cu²⁺, CuNTD generates reactive oxygen species (ROS) storms through photothermal-enhanced cascade catalysis, further inducing mitochondrial dysfunction, ferroptosis and cuproptosis. Multifunctional CuNTD triggers strong ICD through cascade-regulatory pathways of photothermal-amplified ROS storms, cuproptosis and ferroptosis, effectively promoting dendritic cell maturation while reducing monotherapies side effects and resistance. In vivo, CuNTD combined with FDA-approved immunoadjuvants significantly prolong the survival of mice. With its demonstrated biosafety and high efficiency as an ICD inducer, this study provides a promising framework for advancing augmented tumor immunotherapy with significant clinical potential.