An inflammation-modulating ferroptotic nanoplatform for immune-compatible cancer therapy

Chronic tumor-associated inflammation can impair dendritic-cell (DC) antigen presentation and limit immune engagement, posing a barrier to ferroptosis-based therapeutic strategies that often intensify oxidative stress. Here we develop an inflammation-compatible ferroptosis-inducing therapeutic platform by co-integrating an NF-κB-modulating small molecule, celastrol, with an iron-coordinated mesoporous polydopamine carrier (mPDA-Fe-Cel). The platform combines 808-nm photothermal heating with iron redox cycling to promote lipid peroxidation, while concurrently attenuating inflammatory signaling programs, thereby supporting ferroptosis-associated tumor cell damage in a more immune-permissive context. In tumor cells, mPDA-Fe-Cel increases labile Fe²⁺, depletes glutathione, downregulates GPX4, and amplifies lipid peroxidation, consistent with ferroptosis-associated cell death and accompanied by immunogenic cell death hallmarks, including calreticulin exposure, HMGB1 release, and ATP secretion. In parallel, transcriptomic and protein-level analyses indicate attenuation of NF-κB-linked inflammatory programs, with prominent suppression of a CXCL8-centered signature, together with reduced activation of Toll-like receptor and NOD-like receptor pathways. Functionally, tumor-conditioned cues generated by the nanoplatform support DC maturation and antigen-presentation-related phenotypes (MHC-I/MHC-II and costimulatory markers), coinciding with enhanced intratumoral CD8⁺ T-cell infiltration and improved antitumor efficacy in murine models with favorable biosafety. Collectively, this work outlines a materials-based strategy that couples ferroptosis induction with inflammatory modulation to facilitate immune-compatible cancer nanotherapy.