Cell Membrane-Engineered FePDA Nanoparticles Integrate Ferroptosis and Antitumor Immunity.

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.