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.