Injectable hyaluronic acid/polyvinyl alcohol/ferrocene-based hydrogel local delivery platform toward synergistic chemotherapy/ferroptosis therapy of breast cancer.

Polysaccharide hydrogels have significant research significance and application value in fields such as drug delivery and tumor treatment. Herein, a multifunctional injectable polysaccharide hydrogel platform, BFc-PVA/OHA@DOX (BPOD), was designed for the local controllable and long-lasting delivery of doxorubicin (DOX), thereby achieving synergistic chemotherapy and ferroptosis therapy against breast cancer. It was fabricated by physical blending ferrocenediboronic acid (BFc), polyvinyl alcohol (PVA), and oxidized hyaluronic acid (OHA) conjugated with DOX through Schiff base bonds, through the crosslinking of borate ester bonds and hydrogen bonds. It displayed favorable stimulus responsiveness, injectability, self-healing capacity, biodegradability, and biocompatibility, while maintaining the intrinsic Fenton reaction activity of BFc. Within the tumor microenvironment, BPOD enabled the sustained responsive release of DOX and BFc for no less than 10 days. DOX accumulated in tumors through OHA-mediated cellular internalization and induced apoptosis via DNA damage. Meanwhile, BFc generated reactive oxygen species (ROS) and decreased glutathione (GSH) level, thus effectively triggering ferroptosis. Both in vitro and in vivo results demonstrated that BPOD held remarkable anti-breast-cancer activity with reduced systemic toxicity. This work establishes an injectable polysaccharide hydrogel local delivery platform with enhanced cellular internalization, multi-responsive behavior, and synergistic enhancement effects, providing novel technical approaches and strategies for addressing key challenges in clinical treatment of breast cancer.