Co-delivery of fucoxanthin and Twist siRNA using hydroxyethyl starch-cholesterol self-assembled polymer nanoparticles for triple-negative breast cancer synergistic therapy

Background: Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer with an extremely dismal prognosis and few treatment options. As a desmoplastic tumor, tumor cells are girdled by stroma composed of tumor-associated fibroblasts (CAFs) and their secreted stromal components. The rapidly proliferating tumor cells, together with the tumor stroma, exert additional solid tissue pressure on tumor vasculature and surrounding tissues, severely obstructing therapeutic agent from deep intratumoral penetration, and resulting in tumor metastasis and treatment resistance. Fucoxanthin (FX), a xanthophyll carotenoid abundant in marine algae, has attracted widespread attention as a promising alternative candidate for tumor prevention and treatment. Twist is a pivotal regulator of epithelial to mesenchymal transition (EMT), and its depletion has proven to sensitize antitumor drugs, inhibit metastasis, reduce CAFs activation and the following interstitial deposition, increase tumor perfusion, and allow more drugs to be delivered across the tumor stroma. Results: : Herein, our studies proposed a novel self-assembled polymer nanoparticle (siTwist/FX@HES-CH NPs) based on the amino-modified hydroxyethyl starch (HES-NH 2 ) grafted with hydrophobic segment cholesterol (CH). Systematic studies demonstrated that the co-delivery strategy of natural product FX and nucleic acid drug Twist siRNA (siTwist) could not only synergistically kill tumor cells, but also inhibit the CAFs activation and extracellular matrix synthesis. Loose tumor stroma further facilitated transvascular transport and deep penetration of nanoparticles, obviously alleviating the primary tumor burden and inhibiting lung metastasis. Conclusions: : This dually functional nanomedicine that targets both tumor cells and tumor microenvironment (TME) could form a potent anti-TNBC therapeutic cyclical feedback loop, providing a new paradigm for TNBC treatmen t .