Emodin nanoparticles-loaded injectable hydrogel with deep tumor penetration for triple-negative breast cancer therapy

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options, primarily due to poor drug penetration, lack of targets and multidrug resistance (MDR). To overcome these challenges, we developed an injectable sodium alginate (ALG) hydrogel system to enhance penetration and therapeutic efficacy of the natural anticancer compound emodin (EMO). EMO-loaded chitosan nanoparticles (CS-EMO NPs) were first synthesized and combined with hyaluronidase (HAase) before being incorporated into the ALG hydrogel matrix. This novel system demonstrated rapid crosslinking under physiological concentrations of Ca²⁺, sustained drug release, and excellent biocompatibility. It facilitated enhanced penetration and uptake of EMO within the tumor microenvironment, primarily through the specific degradation of hyaluronic acid (HA) by HAase. In vitro, it significantly inhibited the proliferation and migration of 4T1 cells, while also inducing reactive oxygen species (ROS) generation and apoptosis. In vivo, it showed a rapid stable gel formation, ensuring prolonged drug retention and gradual degradation. Notably, the hydrogel triggered a robust antitumor effect in the tumor-bearing mouse model, achieving a tumor growth inhibition rate of 73.23 %. These findings highlight the potential of this injectable hydrogel system as a promising therapeutic approach for TNBC and other challenging cancers.