MicroRNA-Governed Autocatalytic Fenton Nanoplatform for Cancer-Selective Theranostics.

Abstract

Fenton reaction-based chemodynamic therapy (CDT) has emerged as a promising strategy for cancer treatment. However, its efficacy is fundamentally constrained by the limited efficiency of the Fenton reaction and a lack of tumor-selective control. To address these challenges, we develop an intelligent DNAzyme-metal-tannic acid (DzMT) nanoplatform that enables miRNA-regulated intratumoral Fenton reactions for cell-selective imaging-guided CDT. The DzMT system is constructed via coordinated self-assembly of a miRNA-activatable self-blocked DNAzyme, metal ions (Fe³⁺, Fe²⁺, and Mn²⁺), and tannic acid. Upon cellular uptake, the DzMT nanoplatform disassembles under acidic conditions, inducing the efficient release of therapeutic payloads. The liberated DNAzyme is activated by tumor-overexpressed oncogenic miRNAs to produce a strong fluorescence signal for selective cancer imaging. Concurrently, Mn²⁺ serves as a cofactor to activate the unblocked DNAzyme, leading to the cleavage of catalase mRNA. This miRNA-directed gene silencing inhibits H₂O₂ consumption and consequently induces substantial intracellular H₂O₂ accumulation. Fe²⁺ then catalyzes the accumulated H₂O₂ into highly toxic •OH and Fe³⁺ via the Fenton reaction. Meanwhile, the coreleased tannic acid reduces Fe³⁺ back to Fe²⁺, establishing a self-sustaining autocatalytic Fenton cycle that drives continuous •OH generation to eradicate cancer cells. This autocatalytic circuit is autonomously governed by tumor-specific miRNAs, making potent cytotoxicity being restricted to malignant cells while sparing normal tissues. Both <i>in vitro</i> and <i>in vivo</i> evaluations demonstrate high-contrast tumor imaging and effective suppression of tumor growth. This research introduces a class of tumor-specific CDT that transcends conventional material design by leveraging intrinsic biological intelligence for precise and personalized anticancer therapy.