Photodynamic-Photothermal Switching in Osmium-Ferritin Nanoplatform Activates Near Infrared-Driven Tumor Immunity Reprogramming.

Abstract

Conventional metallo-photosensitizers (PSs) face short-wavelength excitation (<650 nm), poor tumor-targeting specificity, and monotherapy limitations; engineering hypoxia-tolerant multimodal systems integrated with tumor-targeting precision and microenvironment-adaptive metallo-PSs remains challenging for clinical transformation. In this study, we developed an Os(II)-cyanine complex <b>OsNIR</b>, which exhibits aggregation-dispersion-induced photodynamic-photothermal conversion properties. To enhance its tumor-targeting capabilities, we encapsulated <b>OsNIR</b> in human heavy-chain ferritin (HFn) to form stable <b>OsNIR@HFn</b> nanoparticles (NPs). <b>OsNIR@HFn</b> NPs exhibit enhanced synergistic photodynamic and photothermal effects coupled with sequential lysosomal-mitochondrial targeting. Upon NIR activation, released <b>OsNIR</b> induces mitochondrial DNA damage, triggering the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) activation and dual apoptosis-ferroptosis mechanisms. In vivo studies confirmed the effectiveness of <b>OsNIR@HFn</b> NPs for bioimaging and metabolic tracking while also demonstrating significant tumor growth inhibition and enhanced immune cell infiltration. In conclusion, this study reports an intelligent phototheranostic system whose functional modality adaptively shifts in response to molecular aggregation-dispersion states. This spatiotemporally regulated immunometabolic activation establishes a linkage between multimechanistic synergy and combinatorial immunotherapy.