Ultrasmall Gold Nanoparticles as “Three-in-One” Enzyme-Mimicking Nanocatalysts for Combined Sonodynamic/Catalytic Therapy in Breast Cancer

The combination of catalytic therapy and sonodynamic therapy (SDT) emerges as a promising approach for the treatment of solid tumors. Smartly designed nanocatalysts can activate tumor-localized catalytic reactions to convert hydrogen peroxide (H₂O₂) into highly toxic hydroxyl radicals (^•OH) while simultaneously generating singlet oxygen (¹O₂) under ultrasound stimulation to induce massive oxidative bursts in cancer cells. However, inadequate levels of endogenous H₂O₂ in tumor tissues and poor sonocatalytic performance of existing nanocatalysts remain major challenges for SDT/catalytic therapy. Self-sufficient nanocatalysts that can generate H₂O₂ within the tumor microenvironment offer a way to continuously power further catalytic reactions, effectively overcoming the limitations of monomodal nanocatalysts. However, such complex nanocatalyst systems with multienzymatic and sonosensitizing properties are often challenging to translate from the bench to the bedside. In this study, we employed ultrasmall gold nanoparticles (usAuNPs) as "three-in-one" multifunctional yet structurally simple nanocatalysts. Under the mildly acidic environment of tumors, usAuNPs were shown to decompose H₂O₂ into ^•OH via peroxidase-like activity and self-supply H₂O₂ by breaking down glucose via glucose oxidase-like activity. Meanwhile, usAuNPs can be activated by ultrasound (1 MHz, 2.0 W/cm²) to generate a significant amount of ¹O₂ (<i>k</i> = 1.78 × 10^-1 min^-1), which is 4-7.5-fold greater than other reported gold nanocomposites. <i>In vivo</i> experiments showed that usAuNP-mediated SDT/catalytic therapy can cause significant suppression of breast cancer growth, achieving a tumor growth inhibition of 90% following a single dose of nanoparticles. Importantly, their ultrasmall sizes facilitate tumor-specific accumulation and rapid clearance from the body via renal filtration, achieving enhanced cancer eradication without significant systemic toxicity. Overall, this work spotlights a potential use of usAuNPs as effective and simple sonocatalysts for combined SDT/catalytic therapy.