Ultrasound/pH Dual-Responsive Cu-Zn-Based Microneedles for Piezo-Sonodynamic and Multimechanism Synergistic Induction of Cuproptosis and Ferroptosis.

Abstract

Sonodynamic therapy is hindered by the insufficient catalytic activity of nanomaterials, the robust antioxidant capacity of the tumor microenvironment, and the limited targeting efficiency of conventional drug delivery systems. In this study, CuSn(OH)6 nanorods were synthesized via coprecipitation. These were then transformed into microspheres through zinc doping and calcination at 500°C under argon, yielding ZnSnO3/Cu0.97Zn0.03 (CZ) nanocomposites. They exhibit excellent piezoelectric catalysis, sonodynamic activity, peroxidase-like activity, and glutathione degradation capacity. These enable the generation of substantial reactive oxygen species under ultrasound (US), which disrupts the redox balance in tumors. Subsequently, FCZ composite drug-loaded microneedles (FCZ-MN) loaded with CZ and 5-fluorouracil (5-Fu) were fabricated. Matrix optimization endowed FCZ-MN with superior mechanical strength and skin biocompatibility, enabling targeted transdermal delivery with pH-responsive and US-controllable drug release. In vitro and in vivo studies have demonstrated that FCZ‑MN combined with US effectively induces ferroptosis, cuproptosis, and apoptosis through multiple pathways, leading to significant tumor suppression without apparent systemic toxicity. This integrated strategy offers a promising alternative to conventional treatment modalities, providing an efficient and well-tolerated platform for localized transdermal tumor therapy.