Cell Membrane‐Engineered FePDA Nanoparticles Integrate Ferroptosis and Antitumor Immunity

ABSTRACT Ferroptosis‐based cancer therapy shows promise in tumor suppression but is often limited by insufficient activation of antitumor immunity. Here, a hepatocellular carcinoma (HCC) targeted nanoplatform was constructed by coating FePDA nanozymes with Hepa1‐6 cell membranes overexpressing ovalbumin (OVA) and CD40 ligand (CD40L), generating tumor membrane‐derived OVA/CD40L‐functionalized FePDA nanoparticles (FePDA‐TMOC). This hybrid architecture integrates homologous tumor targeting with iron homeostasis disruption and co‐stimulatory immune activation within a single nanosystem. Mechanistically, the FePDA core induces sustained depletion of intracellular glutathione (GSH), leading to enhanced lipid peroxidation and promoting ferroptosis by disrupting the GPX4‐SLC7A11 axis. Simultaneously, the OVA/CD40L‐modified membrane promotes efficient uptake by antigen‐presenting cells and enhances pro‐inflammatory immune activation through co‐stimulatory signaling. In vitro experiments demonstrated that FePDA‐TMOC selectively induces ferroptosis in Hepa1‐6 cells and drives macrophage polarization toward a pro‐inflammatory phenotype. Following systemic administration, FePDA‐TMOC preferentially accumulates in tumors, markedly increases CD8 ⁺ T cell infiltration, elevates pro‐inflammatory cytokine levels, and suppresses tumor growth and metastasis without observable systemic toxicity. By integrating ferroptosis induction with antitumor immune activation, this work highlights a rational strategy for transforming immune “cold” tumors into “hot” tumors, providing a potential nanotherapeutic approach for HCC treatment.