Reversing zinc dyshomeostasis and oxidative stress: A metallothionein 1-activating MXene/Zn²⁺ triple-action nanotherapeutic strategy for chronic non-bacterial prostatitis.

Abstract

Chronic non-bacterial prostatitis (CNP), a prevalent and debilitating urological disorder affecting 8.4% of men aged 15-60 years, presents significant clinical challenges due to the paucity of targeted therapies and poor patient adherence. To address this unmet medical need, we developed an innovative multifunctional nanoplatform (QM (Zn) NPs) by integrating Ti₃C₂ MXene with a quercetin-zinc coordination complex (Que-Zn) for precision CNP therapy. This system leverages chondroitin sulfate (Chs)-mediated CD44 targeting to achieve selective accumulation in inflamed prostate tissue, thereby enhancing Zn²⁺ bioavailability while enabling co-delivery of MXene and Que-Zn therapeutic payloads. Upon localization, QM (Zn) NPs orchestrate a coordinated therapeutic cascade: MXene scavenges reactive oxygen species (ROS) <i>via</i> electron-deficient sites, while Que-Zn drives M1-to-M2 macrophage repolarization and facilitates Zn²⁺ cellular uptake. The accumulated intracellular Zn²⁺ critically upregulates metallothionein 1 (Mt1), activating the IKK/NF-κB/IκB axis to resolve inflammation and oxidative damage. Transcriptomic analysis unequivocally identified Mt1 as the pivotal mediator of Zn²⁺-driven microenvironment reprogramming. Notably, QM (Zn) NPs not only significantly alleviated pelvic pain by mitigating neuronal oxidative stress but also exhibited excellent biocompatibility. This work pioneers a targeted nano-theranostic strategy that synergistically restores zinc homeostasis, quenches ROS, and reprograms immune responses, thereby establishing a transformative paradigm for CNP management.