Ultrasound-Driven Cu-Nanobots for Tumor Deep Penetration and Induction of Cuproptosis in Prostate Cancer Therapy.

Cuproptosis has attracted considerable attention in cancer therapy due to its unique ability to circumvent drug resistance, while the in vivo application is hindered by systemic toxicity, rapid clearance, and limited tumor tissue penetration. Widely recognized for its noninvasive application, ultrasound has emerged as a promising method for enhancing drug tumor penetration. In this study, we developed cuproptosis-oriented Nanobots to achieve deep penetration into prostate tumors under ultrasound irradiation. Asymmetric Cu-Nanobots (∼200 nm) were prepared by ultrasound polymerization using hexachlorocyclotriphosphonitrile (HCCP), 4,4'-sulfonyldiphenol (BPS), and tannic acid (TA) as raw materials, which can efficiently load Cu2+ and trigger Cu2+ release at acidic tumor microenvironments. Under ultrasound stimulation, Cu-Nanobots showed obvious directional motion with a velocity of 19.49 μm/s continuously. In vitro cell experiments confirmed that Cu-Nanobots can significantly promote the oligomerization of dihydrolipoamide acetyltransferase (DLAT), downregulate iron-sulfur cluster proteins such as ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS), and induce cuproptosis in human prostate cancer cells. In addition, Cu-Nanobots can effectively penetrate into the deep area of solid tumors in an animal model with a satisfactory tumor inhibition rate of ∼75.75% under sonication. Overall, these ultrasound-driven cuproptosis-oriented Cu-Nanobots provide optimal insights into effective tumor deep penetration and cuproptosis-based treatment.