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ROS-responsive chitosan/hyaluronan polyelectrolyte nanogels for targeted chemo-ferroptosis therapy against breast cancer
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DOI：10.1016/j.ijbiomac.2026.153806.png)
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Abstract
En 中文
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising strategy for combination with chemotherapy in cancer treatment. However, the rational design of delivery systems capable of simultaneously inducing ferroptosis, enhancing chemotherapy efficacy, and reducing systemic toxicity remains a substantial challenge. Herein, we developed a reactive oxygen species (ROS)-responsive, ionically crosslinked chitosan/hyaluronan polyelectrolyte nanogel for targeted chemo-ferroptosis combination therapy. In this system, hyaluronic acid (HA) was first esterified with 1,2-bis (2-hydroxyethylthio) ethylene (BE) and subsequently conjugated with methotrexate (MTX) through a ROS-cleavable linkage, yielding an anionic HA-BE-MTX polymeric prodrug. Protonated chitosan (CS) served as the cationic polymeric component, while sodium tripolyphosphate (TPP) further stabilized the nanogel network through ionic crosslinking. Sorafenib (SOR), a ferroptosis inducer, was physically encapsulated during the ionotropic gelation process. The resulting R-NGMS nanogels were designed to maintain colloidal stability under physiological conditions and to undergo ROS-triggered network loosening and drug release in the tumor microenvironment, where oxidative stress is elevated. This dual-delivery system enabled ROS-responsive MTX release and SOR-mediated ferroptosis induction, thereby promoting ROS accumulation, glutathione depletion, GPX4 suppression, lipid peroxidation, and apoptosis in breast cancer cells. In vivo studies demonstrated that R-NGMS efficiently accumulated in 4T1 tumors through prolonged circulation and HA-CD44-mediated tumor targeting, achieving a tumor growth inhibition rate of 75.85% with reduced systemic toxicity compared with free drug treatment. These findings demonstrate that ionically crosslinked CS/HA-based polyelectrolyte nanogels provide an effective and selective platform for ROS-responsive chemo-ferroptosis combination therapy.
Keywords:
ROS responsive
Nanogel
Ferroptosis
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