Ferroptosis-sensitizing nanoprodrug system for synergistic therapy of triple-negative breast cancer.

Triple-negative breast cancer (TNBC), lacking effective therapeutic targets, is highly aggressive, prone to metastasis, and associated with poor prognosis, highlighting the necessity for innovative therapeutic strategies. Ferroptosis, an emerging form of iron-dependent programmed cell death, presents a promising treatment approach. However, its effectiveness is often hindered by adaptive resistance within the tumor microenvironment and inefficient drug delivery. To address these limitations, the glutathione (GSH)-responsive disulfide linker (-SS-) was utilized to engineer rhein (Rhe, chemotherapeutic agent) and ferrocene (Fc, ferroptosis booster) into the self-assembling small-molecule prodrug RSSF. Sorafenib (SOR), a ferroptosis inducer, was stably loaded into RSSF via a simple nanoprecipitation method, yielding the newly nanoprodrug designated as SOR@RSSF nanoparticles (NPs) for the combination therapy of TNBC. SOR@RSSF NPs exhibit markedly enhanced cellular uptake and enable the highly specific and synchronous release of Rhe, Fc, and SOR in response to intracellular GSH levels. Notably, Fc efficiently generates hydroxyl radicals (•OH) through the Fenton reaction, thereby inducing pronounced oxidative stress, while SOR concurrently impaired the cellular ferroptosis defense machinery. Combined with the chemotherapeutic activity of Rhe, the resulting lipid peroxide (LPO) accumulation and GSH depletion synergistically trigger both ferroptosis and apoptosis selectively in tumor cells. In a 4T1 tumor-bearing mouse model, SOR@RSSF NPs significantly inhibited tumor progression while maintaining a favorable biosafety profile. Overall, this study presents a promising ferroptosis-sensitizing strategy using a nanoprodrug delivery system for combination therapy against TNBC.