Employing Piezoelectric Mg2+‐Doped Hydroxyapatite to Target Death Receptor‐Mediated Necroptosis: A Strategy for Amplifying Immune Activation

Abstract Although immunogenic cell death (ICD) inducers evidently enhance the effectiveness of immunotherapy, their potential is increasingly restricted by the development of apoptosis resistance in tumor cells, poor immunogenicity, and low T‐cell immune responsiveness. In this study, for the first time, piezoelectrically catalyzed Mg 2+ ‐doped hydroxyapatite (Mg‐HAP) nanoparticles, which are coated with a mesoporous silica layer and loaded with ONC201 as an agonist to specifically target the death receptor DR5 on tumor cells, ultimately developing an Mg‐HAP@MS/ONC201 nanoparticle (MHMO NP) system, are engineered. Owing to its excellent piezoelectric properties, MHMO facilitates the release of a significant amount of reactive oxygen species and Ca 2+ within tumor cells, effectively promoting the upregulation of DR5 expression and inducing tumor cell necroptosis to ultimately overcome apoptosis resistance. Concurrently, Mg 2+ released in the tumor microenvironment promotes CD8 + T receptor activation in response to the antitumor immune reaction induced by ICD. Using RNA‐seq analysis, it is elucidated that MHMO can activate the NF‐κB pathway under piezoelectric catalysis, thus inducing M1‐type macrophage polarization. In summary, a dual‐targeting therapy system that targets both tumor cells and the tumor microenvironment under piezoelectric catalysis is designed. This system holds substantial potential for advancements in tumor immunotherapy.