A ROS-responsive degradable hydrogel integrating MnO2 nanoparticles and gemcitabine for synergistic chemodynamic-chemotherapy of breast cancer

A ROS-responsive degradable hydrogel is developed for localized breast cancer therapy. • The hydrogel integrates MnO 2 -mediated chemodynamic therapy with gemcitabine chemotherapy. • Tumor microenvironment-triggered ROS generation accelerates hydrogel degradation and drug release. • The self-amplifying therapeutic cascade enhances antitumour efficacy with favourable biosafety. Breast cancer therapy remains limited by systemic side effects, intratumoral drug accumulation and tumor recurrence, highlighting the need for effective localized treatment strategies. Herein, we develop a reactive oxygen species (ROS)-responsive degradable hydrogel for localized chemodynamic-chemotherapeutic breast cancer therapy. Bovine serum albumin-templated MnO 2 (BM) nanoparticles and gemcitabine (Gem) are incorporated into a thiol-norbornene photocrosslinked polyethylene glycol (PEG) network containing ROS-cleavable thioketal (TK) linkers. Such a hydrogel serves not only as a local drug depot, but also a tumor microenvironment-activated therapeutic system. Within this microenvironment, MnO 2 consumes endogenous glutathione (GSH) and reacts with hydrogen peroxide (H 2 O 2 ) to generate Mn 2+ and hydroxyl radicals (·OH), inducing oxidative damage and perturbing tumour redox homeostasis. The resulting ROS further cleave TK linkers, accelerating hydrogel degradation and Gem release. This self-amplifying feedback couples chemodynamic therapy with chemotherapy, enabling localized, stimuli-responsive drug delivery and enhanced antitumour efficacy. In vitro and in vivo evaluations confirm significant tumor suppression and favourable biosafety. These findings highlight a microenvironment-responsive hydrogel platform for regional combination therapy of breast cancer. Download: Download high-res image (207KB) Download: Download full-size image A ROS-responsive degradable hydrogel is designed for localized chemo-chemodynamic breast cancer therapy. BSA-templated MnO 2 nanoparticles and gemcitabine are encapsulated within a thiol-norbornene photocrosslinked PEG hydrogel containing ROS-cleavable thioketal linkers. After implantation at the tumor site, MnO 2 reacts with tumor-overexpressed glutathione and hydrogen peroxide to generate Mn 2+ and hydroxyl radicals, thereby depleting intracellular antioxidants and enhancing chemodynamic therapy. The elevated ROS simultaneously cleave thioketal linkers, triggering hydrogel degradation and accelerating gemcitabine release. This tumor microenvironment-activated cascade integrates ROS-amplified chemodynamic therapy with localized chemotherapy, achieving potent tumor cell killing and improved therapeutic safety.