In situ thermosensitive H2O2/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 H₂O₂-deficient tumor microenvironment (TME). To address this issue, we have developed calcium peroxide (CaO₂) nanoparticles capable of supplying O₂/H₂O₂, 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 in vitro for their anticancer activity in 4T1 cells. To address challenges related to specificity and frequent dosing, we developed an in situ thermosensitive injectable hydrogel incorporating CPIR nanoparticles. Cross-linking at 60 °C creates a self-sufficient formulation, releasing NO/H₂O₂ to combat tumor hypoxia. RSL-3 induces ferroptosis, contributing to a synergistic photothermal effect and eliminating tumor in vivo.