Sequence-Responsive Multifunctional Supramolecular Nanomicelles Act on the Regression of TNBC and Its Lung Metastasis via Synergic Pyroptosis-Mediated Immune Activation.

Abstract

Design of effective nanodrugs to modulate the immunosuppression of tumor microenvironment is a desirable approach to boost the clinical tumor-therapeutic effect. Supramolecular nanomicelles PolyMN-TO-8, which are constructed by self-assembling supramolecular host MTX-MPEG2000, guest NPX-2S, and TO-8 through hydrophobic forces, have excellent stability and responsiveness to carboxylesterase and glutathione in turn. In vivo studies validate that PolyMN-TO-8 enable to trigger pyroptosis-mediated immunogenic cell death under laser, avoiding the occurrence of immune dysregulation simultaneously. This therapeutic mode strengthens dendritic cells' maturation and accelerates the infiltration of CD8+ T cells into tumors through moderate activation of pro-inflammatory factors with elimination of immune-escape, ultimately making the tumor inhibition rate as high as 87.44% via synergistic functions of photodynamic therapy, photothermal therapy, chemotherapy, etc. The loss of immune-escape quickens the infiltration of CD8+ T cells into lungs, and further eschews the generation of tumor nodules in it. Chemotherapy, the release of interferon-γ, and immune memory effect also strengthen the defense against metastasis. The generation of O2 catalyzed by PolyMN-TO-8 under laser is indispensable for tumor metastasis inhibition undoubtedly.