In situ thermosensitive H 2 O 2 /NO self-sufficient hydrogel for photothermal ferroptosis of triple-negative breast cancer

L-Arginine (LA), a semi-essential amino acid in the human body, holds significant potential in cancer therapy due to its ability to generate nitric oxide (NO) continuously in the presence of inducible NO synthase (iNOS) or reactive oxygen species (ROS). However, the efficiency of NO production in tumor tissue is severely constrained by the hypoxic and H O -deficient tumor microenvironment (TME). To address this issue, we have developed calcium peroxide (CaO ) nanoparticles capable of supplying O /H O , which encapsulate and oxidize an LA-modified lipid bilayer to enable controlled localized NO generation in the presence of ROS, synergising with a ferroptosis inducer, RSL-3 (CPIR NPs). The synthesized nanoparticles were tested for their anticancer activity in 4T1 cells. To address challenges related to specificity and frequent dosing, we developed an thermosensitive injectable hydrogel incorporating CPIR nanoparticles. Cross-linking at 60 °C creates a self-sufficient formulation, releasing NO/H O to combat tumor hypoxia. RSL-3 induces ferroptosis, contributing to a synergistic photothermal effect and eliminating tumor .