Ultrasound-Activated FeSnO(OH)5/Cu2S Heterojunction Microneedles Coordinate Redox Catalysis and Metal-Ion Dyshomeostasis for Localized Tumor Therapy.

An ultrasound-activated microneedle patch (FCSP-MN) was developed for localized tumor therapy by integrating FeSnO(OH)5/Cu2S heterojunction nanoparticles (FCS) and phloretin into pH-responsive poly(acrylic acid)/poly(vinylpyrrolidone) microneedle tips. Heterojunction formation promoted interfacial charge redistribution, with approximately 1.942 electrons transferred from Cu2S to FeSnO(OH)5, and reduced the calculated energy barrier of the rate-determining peroxidase-like step from 2.38 to 2.03 eV. Consequently, FCS enhanced ultrasound-triggered singlet oxygen and hydroxyl radical generation, peroxidase-like catalysis, and glutathione depletion, thereby amplifying oxidative stress. The microneedles enabled efficient skin penetration and acidity-responsive delivery, releasing approximately 80% of phloretin at pH 5.4 vs 40% at pH 7.4 within 80 min, while ultrasound accelerated tip dissolution. In 4T1 cells, FCS and phloretin (FCSP) combined with ultrasound induced pronounced oxidative and mitochondrial damage accompanied by ferroptosis- and cuproptosis-associated responses, including lipid peroxidation, glutathione peroxidase 4 suppression, and dihydrolipoamide S-acetyltransferase oligomerization. In 4T1 tumor-bearing mice, FCSP-MN plus ultrasound achieved the strongest tumor-growth suppression among the tested treatments, with stable body weight and no obvious histological injury to major organs. This platform couples heterointerface-enhanced redox catalysis, responsive local delivery, and Fe/Cu dyshomeostasis for multimodal tumor therapy.