pH-responsive silk fibroin/chitosan nanoparticles functionalized with chondroitin sulfate for CD44-targeted delivery of curcumin in breast cancer cells

The rational design of multifunctional nanoparticles offers a promising strategy to improve precision and therapeutic efficacy of cancer chemotherapy. In this study, we report the development of novel pH-responsive silk fibroin (SF) nanoparticles (NPs), integrated with chitosan (CH) and covalently conjugated to chondroitin sulfate (CS), specifically engineered for targeted delivery of curcumin (Cur) to MDA-MB-231 breast cancer cells. The drug loading was evaluated across drug-to-polymer ratios of 5 %, 6 %, 10 %, and 20 %, with the 10 % ratio selected as optimal. Notably, the incorporation of CH into the NPs structure significantly increased both drug- loading efficiency and loading capacity, likely due to hydrogen bonding interactions between CH functional groups and Cur. The optimized CS-modified SF/CH NPs demonstrated an average size of ∼188 nm, favorable polydispersity index (0.15), and excellent colloidal stability in aqueous environments. In vitro release studies revealed a much faster Cur release rate under acidic pH conditions, mimicking the tumor microenvironment. Furthermore, Cur-loaded modified NPs exhibited enhanced cytotoxicity compared to unmodified NPs. Meanwhile, Cellular uptake of Cur-loaded CS-modified SF/CH NPs occurred predominantly via CD44 receptor–mediated endocytosis, as indicated by a significant decrease in internalization in the presence of free CS. Moreover, CS-modified SF/CH NPs induced a higher apoptotic response (67.8 %) compared to unmodified SF/CH NPs (58.8 %). These results underscore the significant potential of CS-modified SF/CH NPs as an efficient and targeted delivery platform, offering both enhanced therapeutic efficacy and selective cytotoxicity of Cur, and provide a promising strategy for precision chemotherapy in aggressive breast cancer treatment.