Sialic acid-modified phosphorene for low-necrosis and targeted drug delivery in breast cancer

Targeted drug delivery continues to face significant challenges in cancer therapy, necessitating innovative materials and methods that enhance treatment efficacy while minimizing systemic toxicity. In this study, we introduce a straightforward and solvent-free method for synthesizing black phosphorus (BP) nanosheets directly on silicon substrates via hydrogen-plasma treatment, followed by immediate functionalization with sialic acid (SA) molecules. This technique yields a stable, biocompatible phosphorene-based platform (called DSAP), characterized by its high loading capacity for the anticancer drug doxorubicin (DOX). The functionalization and stability of the nanosheets were rigorously evaluated using Raman spectroscopy, electron microscopy, X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and high-resolution transmission electron microscopy (HR-TEM). The functionalized nanosheets demonstrated enhanced stability against degradation in aqueous environments. Notably, DSAP exploits Siglec-SA interactions for receptor-mediated uptake, ensuring precise tumor targeting. Zeta potential measurements confirmed efficient DOX adsorption onto DSAP. In vitro studies using MDA-MB-231 breast cancer cells revealed a significant enhancement in apoptotic cell death upon treatment with DSAP compared to treatment with mere DOX, as evidenced by high early and late apoptosis rates and substantially reduced necrosis. Electron microscopy provided a visual confirmation of these apoptotic effects, capturing distinct cellular features, such as membrane blebbing and chromatin condensation, indicative of receptor-driven programmed cell death. By uniting the innate biodegradability of BP nanosheets with the specificity imparted by SA, DSAP offers a transformative leap forward in cancer nanomedicine, potentially extendable to additional therapeutic approaches (e.g., photothermal or photodynamic therapies) without sacrificing biocompatibility. These results position DSAP as a next-generation platform for precision drug delivery, paving the way for safer, more effective, and highly personalized cancer treatments.