Spatiotemporally Engineered POSS Nanoplatform for Multi‐Organelle‐Targeted Synergistic Photothermal‐Chemo‐Immunotherapy

ABSTRACT Tumor heterogeneity and immunosuppression limit the efficacy of conventional immunotherapy. Here, we introduce a spatiotemporally engineered nanoplatform ( CAP/CyOH@NPs ) that achieves multi‐organelle targeting in tumor cells through POSS‐based nanoconfinement. The rigid POSS cage co‐encapsulates a photothermal agent (CyOH) and chemotherapeutic prodrug (capecitabine), enabling stable, simultaneous localization to lysosomes, mitochondria, and the endoplasmic reticulum‐independent of pH or membrane potential. This subcellular precision enhances photothermal conversion (53.4%) and amplifies immunogenic cell death via coordinated organelle stress. When combined with PD‐L1 blockade, the platform remodels the tumor immune microenvironment and suppresses both primary and distant tumors in a 4T1 breast cancer model. This work establishes a new paradigm for engineering nanomedicines with organelle‐level specificity, offering a versatile strategy to overcome resistance in precision oncology.