Pyroptosis is an
inflammation-dependent and self-cascade amplifying type of programmed cell death, serving as an effective means for activating the local immune response and improving the anticancer efficacy. As the effector of pyroptosis, gasdermin-E (GSDME) is silenced in most
tumor cells. The gene silencing can be reversed by DNA demethylation, but the systemic side effects and toxicity of chemotherapeutic agents are inevitable. In this work, inhaled
poly(lactic-co-glycolic acid) (PLGA) porous
microspheres loaded with
Decitabine (DAC) and
Doxorubicin (DOX) (denoted as CO-MPs) were prepared to induce cell pyroptosis for orthotopic
lung cancer therapy with fewer systemic side effects. The CO-MPs showed a hollow and porous spherical morphology and exhibited an excellent aerodynamic property, lung distribution and a sustained release effect. The CO-MPs could reverse GSDME silencing and elevate the expression of cleaved-
caspase 3 in
tumor cells. The cleaved-
caspase 3 protein cleaved the GSDEM
protein to obtain GSDME-N
protein, causing the
rupture of cell plasma membranes, release of cell contents and activation of the immune system. The CO-MPs could lead to the suppression of lung
tumors, the decrease of the lung metastatic nodules in
tumor-bearing mice and the induction of immunological memory that provides continuous protection from the
tumor rechallenge. The inhalable
microspheres loaded with DAC and DOX could be an effective strategy for
lung cancer treatment via the pyroptosis mechanism.