Anionic Hofmeister Effect Differentiated Subcellular Distributions of pH-Responsive Metal-Organic Cages for Tumor...

The precise control of subcellular distribution offers significant advantages for advancing the understanding of cellular biology and targeted theranostics strategies. Herein, we report anionic Hofmeister effect triggered allostery of pH-responsive metal-organic cage MOC-68, which regulates the subcellular distributions with the salting-out MOC-68-BF₄ exhibiting preferential cell membrane anchoring, while the salting-in MOC-68-Cl demonstrating more endocytosis for lysosome targeting. Owing to the integration of multi-functionalities of protonating imidazole moieties, conformationally adaptive amine vertices, and microsecond luminescent lifetimes into a nanocage, these MOCs show pH-responsive singlet oxygen (¹O₂) generation through energy transfer pathways, and achieve microenvironment-programmed photodynamic precision by anchoring MOC-68-BF₄ to near-neutral cell membranes whereas enriching MOC-68-Cl in acidic lysosomes, which drives spatially resolved ¹O₂ generation gradients via protonation-optimized metal-to-ligand charge transfer. Moreover, MOC-68-Cl achieves superior photocytotoxicity through PANoptosis-mediated immunogenic cell death, driving primary tumor ablation via localized ¹O₂ burst while systemically activating T cell-dependent adaptive immunity to concurrently suppress tumor progression and inhibit lung metastasis. This work highlights the potential of anion-mediated biological behaviors of MOCs, providing a way to advance nanocage biomedicine for future precision theranostic applications.