Amplifying Lipid Peroxidation via a Cascade Nanozyme with Lipid Metabolism Reprogramming for Enhanced Chemodynamic Therapy.

Abstract

The therapeutic efficacy of chemodynamic therapy (CDT) is severely constrained by insufficient endogenous hydrogen peroxide (H2O2), excessive glutathione (GSH)-mediated scavenging of hydroxyl radicals (·OH), and the limited abundance of lipid peroxidation (LPO) substrates due to low membrane unsaturation in tumor cells. To address these challenges, we herein develop a tumor microenvironment (TME)-responsive, multifunctional mesoporous multimetallic nanozyme (CuPtAu, CPA) loaded with the lipid metabolism modulator oleanolic acid (OA) and further coated with hyaluronic acid (HA), constructing a targeted nanoplatform (CPA/OA@HA). This system achieves tumor-specific enrichment via HA-mediated CD44 targeting and responsively releases OA within the TME, which significantly increasing the proportion of polyunsaturated fatty acids (PUFAs), thereby providing abundant substrates for LPO. Concurrently, the CPA nanozyme exhibits intrinsic glucose oxidase (GOx)-, catalase (CAT)-, and peroxidase (POD)-mimicking activities, enabling self-supply of H2O2 and O2, sustained generation of ·OH, and efficient depletion of GSH. Through a dual synergistic strategy of substrate enhancement and catalytic amplification, CPA/OA@HA potently propagates the LPO chain reaction, inducing irreversible oxidative damage to tumor cells. Both in vitro and in vivo results demonstrate remarkable tumor suppression at low doses with excellent biocompatibility. This metabolic intervention-integrated CDT strategy provides a paradigm to overcome oxidative resistance in cancer therapy.