Bimetallic nanoconjugate hijack Fe-S clusters to drive a closed-loop cuproptosis-ferroptosis strategy for osteosarcoma inhibition.

Cuproptosis and ferroptosis are difficult to synergize in tumor suppression due to their spatiotemporal asynchrony and mechanistic dispersion. Therefore, we proposed a new paradigm of Ferroptosis-Cuproptosis self-recycling. An iron‑sulfur cluster (Fe-S) metabolic collapse was constructed by hyaluronic acid (HA)-functionalized bimetallic nano-enzymes (HA@CuCo-NC) to initiate this tumoricidal mechanism. HA@CuCo-NC specifically accumulates in osteosarcoma cells through HA-mediated targeting. The multi-enzyme activity triggers a surge of reactive oxygen species (ROS) in the tumor microenvironment, which, along with Co2+, induces ferroptosis. This leads to severe mitochondrial damage and glutathione (GSH) depletion, which in turn activates the cuproptosis cascade. Cuproptosis causes Fe-S protein degradation and Fe2+ release into the labile iron pool (LIP) by inhibiting Fe-S cluster formation and dihydrolipoamide acetyltransferase (DLAT) oligomerization. The released Fe2+ enhances oxidative stress and promotes membrane disassembly via the Fenton reaction. The two act synergistically to form a dynamic self-reinforcing cycle: Ferroptosis-related mitochondrial damage exacerbates the toxicity of Cu2+. Cuproptosis-released Fe2+ further activates ferroptosis. In vivo experiments demonstrated that HA@CuCo-NC significantly inhibited the growth of osteosarcoma in situ without causing systemic toxicity. This research introduces a novel approach to treating solid tumors by reconstructing the metabolic interaction network of copper and iron.