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 (H 2 O 2 ) level. Herein, we present a method for H 2 O 2 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 Cu 2+ and CAT siRNA and then modified with hyaluronic acid (HA) for active tumor targeting. After tumor cell uptake, the released Cu 2+ is reduced by highly expressed glutathione (GSH) to Cu +, which then catalyzes H 2 O 2 to produce toxic hydroxyl radicals ( • OH) to kill tumor cells. CAT siRNA can efficiently silence the CAT mRNA to inhibit the consumption of H 2 O 2, resulting in H 2 O 2 accumulation. The Cu 2+ -mediated GSH elimination and siRNA-induced endogenous H 2 O 2 enrichment both potentiate CDT. Cu-siRNA@HA exhibits good biocompatibility and therapeutic efficiency. This work thus paves a new way to supply H 2 O 2 in CDT and may hold potential for clinical application.