Dihydroartemisinin-Loaded ZIF-8 Nanoparticles Elicit Chemo-Immunotherapy against Malignant Pleural Effusion via Inhibition of OCT4/M-CSF Signaling Pathway

Malignant pleural effusion (MPE) is the most common complication of lung cancer with an extremely high lethality, for which no effective chemotherapeutic agent is available. Activation of local antitumor immunity of MPE while selectively destroying the malignant cells represents an effective strategy in recent years. Herein, we sought to figure out whether dihydroartemisinin (DHA), whose pleiotropic antilung cancer effects have been elucidated by our team, loaded with zeolite imidazole framework-8 (ZIF-8) could serve as a novel anti-MPE chemo-immunotherapeutic strategy. The synthesized DHA@ZIF-8 nanoparticles were characterized in terms of size, potential, elemental composition, and stability, while the drug loading efficiency of DHA was calculated for further research. Based on it, human-derived MPE cells (hMPEC) were isolated, cultured, and identified, which was utilized together with lung cancer cell lines to validate the in vitro chemotherapeutic toxicity of DHA@ZIF-8. The prolonged survival of MPE mice treated with DHA@ZIF-8 was observed with reduced volume of MPE compared with the control group, as evidenced by micro-CT and ultrasonic images. More impressively, DHA@ZIF-8 effectively promoted the M1 polarization and dampened M2 polarization of macrophages in MPE, wherein the differentially expressed genes (DEGs) were enriched in the OCT4/NF-κB signaling pathway, which is the upstream of M-CSF. Further investigations presented zinc ions and DHA released from the DHA@ZIF-8, which located in lysosome, acted as a direct inhibitor of OCT4. However, overexpression of OCT4 attenuated the DHA@ZIF-8's effects on the NF-κB/M-CSF signaling. Taken together, the hMPEC and mice in situ models were constructed by our team for the first time, wherein DHA@ZIF-8 exhibits potent chemotherapeutic efficacy in these models. DHA@ZIF-8 facilitates M1 polarization of macrophages through the depression of the OCT4/NF-κB/M-CSF signaling pathway to enhance immunotherapeutic efficacy simultaneously, which provides a critical basis for DHA and bionanomaterial application in MPE treatment in the future.