Silencing the Catalase Gene with SiRNA for Enhanced Chemodynamic Therapy

Chemodynamic therapy (CDT) has been emerging as a promising strategy for cancer treatment. But the CDT efficiency is restricted by the insufficient intracellular hydrogen peroxide (H₂O₂) level. Herein, we present a method for H₂O₂ accumulation in tumor cells by silencing the catalase (CAT) gene with siRNA to achieve enhanced CDT. Cu-siRNA nanocomposites are fabricated by self-assembly of Cu²⁺ and CAT siRNA and then modified with hyaluronic acid (HA) for active tumor targeting. After tumor cell uptake, the released Cu²⁺ is reduced by highly expressed glutathione (GSH) to Cu⁺, which then catalyzes H₂O₂ to produce toxic hydroxyl radicals (^•OH) to kill tumor cells. CAT siRNA can efficiently silence the CAT mRNA to inhibit the consumption of H₂O₂, resulting in H₂O₂ accumulation. The Cu²⁺-mediated GSH elimination and siRNA-induced endogenous H₂O₂ enrichment both potentiate CDT. Cu-siRNA@HA exhibits good biocompatibility and therapeutic efficiency. This work thus paves a new way to supply H₂O₂ in CDT and may hold potential for clinical application.