The activation of ferroptosis presents a versatile strategy for enhancing the antitumor immune responses in cancer therapy. However, developing ferroptosis inducers that combine high biocompatibility and therapeutic efficiency remains challenging. In this study, we propose a novel approach using biological nanoparticles derived from outer membrane vesicles (OMVs) of Escherichia coli for tumor treatment, aiming to activate ferroptosis and stimulate the immune responses. Specifically, we functionalize the OMVs by anchoring them with ferrous ions via electrostatic interactions and loading them with the STING agonist-4, followed by tumor-targeting DSPE-PEG-FA decoration, henceforth referred to as OMV/SaFeFA. The anchoring of ferrous ions endows the OMVs with peroxidase-like activity, capable of inducing cellular lipid peroxidation by catalyzing H 2 O 2 to • OH. Furthermore, OMV/SaFeFA exhibits pH-responsive release of ferrous ions and the agonist, along with tumor-targeting capabilities, enabling tumor-specific therapy while minimizing side effects. Notably, the concurrent activation of the STING pathway and ferroptosis elicits robust antitumor responses in colon tumor-bearing mouse models, leading to exceptional therapeutic efficacy and prolonged survival. Importantly, no acute toxicity was observed in mice receiving OMV/SaFeFA treatments, underscoring its potential for future tumor therapy and clinical translation.
Owing to the deficiency of infiltrating immune cells and the accumulation of immunosuppressive cells in tumor microenvironment (TME), immunotherapy remains enormous challenges in colorectal cancer (CRC). Here, CRC was found to be sensitive to cuproptosis which could further evoke immune responses and mediate immune resistance. Thus, a cuproptosis-mediated immunotherapy nanoreactor (CCJD-FA) was constructed by encapsulating copper-based shell-coated CaO 2 and bromodomain-containing protein 4 inhibitor JQ-1 with DSPE-PEG-FA. Within tumor cells, CCJD-FA was disassembled under GSH environment, and the exposed CaO 2 could generate H 2 O 2 under the acidic condition, which reacted with the released Cu 2+ via Fenton-like reaction to produce O 2 for relieving hypoxia and Cu + for inducing cuproptosis. Furthermore, CCJD-FA could also inhibit intracellular glycolysis and ATP generation, then blocking the Cu + efflux protein ATP7B. Meanwhile, the IFN-γ-induced PD-L1 expression could be exactly reduced by the BRD4 suppression and oxygen supply. These effects sensitized cancer cells to cuproptosis, further evoking systemic immune responses and reshaping immunosuppressive TME to inhibit tumor growth.
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