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

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) via 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.