Carrier‐Free Self‐Assembled Nanoparticles for Triple‐Amplified Tumor Chemodynamic Therapy and Cuproptosis Induction

The carrier-free self-assembled CuDL@CM nanoparticles integrated H₂O₂ self-supplying and GSH depletion are constructed for triple-amplified tumor chemodynamic therapy and cuproptosis induction. The tumor cell membrane-camouflaged nanoparticles exhibit excellent targeting capabilities and remarkable antitumor efficacy in vitro and in vivo via triple boosting chemodynamic strategy, offering a promising avenue for improving cancer treatment outcomes and new insights for multimodal cancer therapy.

Abstract

Chemodynamic therapy (CDT) holds great promise in cancer treatment, whereas its efficacy is severely compromised by the low concentration of endogenous hydrogen peroxide(H₂O₂), insufficient exogenous catalytic ions, and the presence of high levels of cellular glutathione (GSH). Herein, a dissociable, tumor cell membrane-camouflaged carrier-free nanoparticle is developed through the molecular interaction of copper ions (Cu²⁺), dequalinium (DQ), and β-Lapachone (β-Lap). Upon homotypic tumor targeting, the system releases Cu²⁺ (exogenous catalytic ions), β-Lap (H₂O₂ donor), and DQ (GSH scavenger), achieving triple amplification of CDT efficacy. Concurrently, the intracellular accumulation of Cu²⁺ induces cuproptosis, thereby synergistically augmenting CDT efficacy and strikingly restraining tumor growth. Overall, the integration of Cu²⁺ supplementation, H₂O₂ self-supplying, and GSH depletion offers a promising avenue for improving cancer treatment outcomes and paves a new way for multimodal cancer therapy.