Biomimetic bacteria-derived nanoclusters enhance ferroptosis cancer immunotherapy through synergistic CRISPR-photothermo modulation

The induction of ferroptosis in cancer cells has emerged as a promising approach to initiate immunogenic cell death (ICD). However, the limited production of lipid peroxidation (LPO) considerably undermines the effectiveness of ferroptosis. In this work, T7 polypeptide engineered bacterial outer membrane vesicles (T7-OMVs) co-delivering plasmids and melanin nanoparticles (MNPs) are fabricated into nanoclusters (TO@Mp) for LPO amplification. The clustered regularly interspaced short palindromic repeats (CRISPR) system as the gene editing tool can knockdown glutathione peroxides 4 (GPX4) to amplify LPO accumulation. Photothermal MNPs exhibit an intrinsic capacity of up-regulating Acyl-CoA synthetase long chain family member 4 (ACSL4) and generating reactive oxygen species (ROS), thereby cooperating with GPX4 gene knockdown to reinforce ferroptosis. While the TO@Mp NPs augment ICD via synergistic lipid peroxidation induced ferroptosis, the mechanism of proinflammatory response acquired by the RNA-seq analysis also indicates that the nanoclusters activate the toll like receptor (TLR) pathways, thereby coordinately potentiating DCs maturation and T cells immunity to restrain tumor growth and metastasis. Conclusively, the biomimetic bacteria-derived platform for synergistic CRISPR-photothermo modulation represents an appealing way for tumor suppression and immunological therapy, which holds great potential in clinical translation for cancer treatment.