https://doi.org/10.1016/j.apsb.2022.11.002
Pyroptosis provides a new window for relieving the tumor immunosuppressive microenvironment (TIM) and promoting systemic immune responses for tumor treatments. However, gasdermin D (GSDMD), a key protein in the pyroptosis process mediated by caspase-1, is low expressed in the majority of tumor cells and small-molecule inhibitors of DNA methylation suffer from nonspecific or single-function defects.
To address these issues, hexahistidine (His6)-metal assembly (HmA) was employed as the drug delivery vector to load nigericin (Nig) and decitabine (DAC) affording a dual-drug delivery system (Nig + DAC)@HmA. The (Nig + DAC)@HmA nanoparticles are efficiently internalized by cells through endocytosis, easily escape from the lysosome, and are highly distributed in the tumor sites. DAC up-regulates the expression of GSDMD which is then cleaved by the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and caspase-1 protein activated by Nig. Effective cancer cell pyroptosis is thus achieved and induces a significant systemic antitumor immunity for impressive tumor suppression with negligible side effects in vivo.
The results of this research suggest that such an easy-to-manipulate self-assembled nano-system (Nig + DAC)@HmA provides a new anticancer path by enhancing pyroptosis through reinforced inflammation.
Keywords: Self-assembled nanoparticle, Pyroptosis, NLRP3, GSDMD, InflammationIL-8, Immunotherapy responses, Solid tumor
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383522004543-ga1_lrg.jpg
The mechanism of (Nig + DAC)@HmA cell pyroptosis for tumor immunotherapy. Pyroptotic cancer cells in primary tumor secret pro-inflammatory cytokines to reprogram tumor-associated macrophages from M2 to M1 for immunotherapy.
