Ozone-loaded nano/micro-oil droplets induce senescence-associated immunogenicity via intracellular glycation.

Cancer cells exhibit elevated metabolic activity that fuels proliferation while maintaining redox homeostasis to survive oxidative stress. Therapeutic strategies that can precisely target both tumor metabolism and the remodeled tumor microenvironment remain major challenges in cancer treatment. To address this, we engineered a saponin-emulsified nano/micro-sized oil droplet system (NOD(O)) for efficient ozone delivery. Following cellular endocytosis, NOD(O) localizes to lysosomes, where the surfactant of saponin promotes lysosomal membrane permeabilization (LMP) and releases NOD(O) into the cytoplasm. The delivered ozone triggers intracellular oxidative stress, generating reactive oxygen species (ROS). Notably, we demonstrate that ozone delivery promotes intracellular glycation reactions, leading to advanced glycation end-product (AGE) accumulation, which induces cellular senescence and reduces nuclear proliferative activity. Furthermore, these disruptive processes elicit immunogenic cell death (ICD), as evidenced by suppressed tumor growth and robust immune cell infiltration in tumor tissues in vivo. Collectively, this work establishes an effective ozone delivery platform and introduces a strategy that leverages ozone-driven intracellular glycation and senescence for enhanced cancer therapy.