Tumor microenvironment-regulated nanoplatform for enhanced chemotherapy, cuproptosis and nonferrous ferroptosis combined cancer therapy

Therapeutic approaches combining various treatments have attracted intensive interests for tumor therapy. Nevertheless, these strategies still face many obstacles, such as overexpressed GSH and hypoxia, owing to the intricate tumor microenvironment (TME). Herein, a versatile nanoplatform, CeO₂@CuO₂@DOX-RSL3@HA (CCDRH), was initially constructed for promoting the antitumor efficiency <i>via</i> regulation of the TME. The CCDRH was prepared taking mixed valence CeO₂ as the nanocarrier, followed by the attachment of CuO₂ nanodots, DOX and RSL3 and the camouflaging of hyaluronic acid. The CuO₂ could disassemble in the acidic TME to release Cu²⁺ and H₂O₂. The POD- and CAT-mimicking activities of CeO₂ could convert H₂O₂ to ˙OH and O₂, leading to the enhancement of chemo-chemodynamic therapy. Meanwhile, RSL3 could effectively suppress GPX4 expression, and the overloaded Cu²⁺ and Ce⁴⁺ could deplete excess GSH, resulting in an intensive accumulation of LPO and significant nonferrous ferroptosis. Additionally, Cu⁺ induces the oligomerization of lipoylated DLAT and downregulates iron-sulfur cluster proteins, resulting in potent cellular cuproptosis. The experimental results revealed that CCDRH exhibited high performance in tumor inhibition, which is attributed to the combined effect of enhanced chemotherapy, ferroptosis and cuproptosis. The study provides a new approach for improving anticancer efficiency <i>via</i> regulation of the TME.