A POSS-Based Metal-Phenolic Network with Coupled Hardness and Softness for Photodynamic-Immunotherapy of Triple-Negative Breast Cancer

To overcome the oxidative stress and resistance of cancer stem cells (CSCs) for successful metastatic triple-negative breast cancer (TNBC) treatment, we report polyhedral oligosilsesquioxanes (POSS)-based metal-phenolic networks (MPNs) that integrate hard POSS as a rigid dendritic macromolecular moiety for binding with a photosensitizer (PS), Chlorin e6 (Ce6) to improve the reactive oxygen species (ROS) generation efficiency of photodynamic therapy (PDT), and soft metal ions for dynamic coordination-driven co-self-assembly with POSS and an antiapoptotic protein inhibitor, sabutoclax (Sab) to afford MPN nanoparticles (NPs). The MPN NPs show the most significant inhibitory effect in a 4T1 TNBC proximal/distal tumor model with a tumor growth inhibition (TGI) value of 96.8% and significant distal tumor growth inhibition via simultaneous immunogenic cell death (ICD) induction, tumor-associated macrophages (TAMs) polarization, and CSCs elimination. This study presents a facile approach toward the first POSS-based metal-phenolic network with coupled hardness and softness for highly efficient photodynamic immunotherapy of TNBC.