Development of pH-responsive ZIF-8-based multimetallic redox nanoreactors for ferroptosis-mediated cancer therapy.

Triple-negative breast cancer (TNBC) lacks effective tumor-selective strategies, particularly limiting ferroptosis-based therapies that depend on oxidative stress. Here, we develop a structurally reinforced ternary redox-cycling nanoreactor that integrates Zr4⁺-stabilized zeolitic imidazolate framework-8 (ZIF-8) with redox-active Cu/Mn centers and ultrasmall Au nanodots, while co-loading paclitaxel (PTX) for acidic tumor microenvironment-responsive release. The Cu-Mn-Au interfaces enable rapid electron shuttling, sustaining multivalent metal cycling, accelerating Fenton-like reactive oxygen species (ROS) generation, depleting GSH, and promoting lipid peroxidation. Density functional theory (DFT) calculations further support its self-perpetuating redox mechanism. Dual surface modification with 4 T1 cell membranes and folic acid confers homotypic and receptor-mediated targeting. Mechanistic studies reveal coordinated GPX4/SLC7A11 suppression, PTX-enhanced cell-cycle arrest, and NCOA4/HO-1-mediated ferritinophagy, collectively amplifying ferroptosis. Unlike conventional metal-organic frameworks (MOFs), this Zr-reinforced trimetallic system maintains continuous redox cycling under reductive conditions. Overall, the nanoreactor achieves sustained ROS amplification, iron-homeostasis remodeling, and enhanced tumor-selective ferroptosis, offering a promising therapeutic strategy for TNBC.