T-cell activity feedback-guided photothermal immunotherapy enabled by immune-responsive redox nanodots

Immunogenic cell death (ICD)-based tumor therapies are fundamentally limited by the absence of real-time immune activity readouts and by dysregulated oxidative stress during treatment, which together undermine immune preservation and therapeutic consistency. To address these challenges, an ultrasmall polychlorogenic acid nanodot platform, termed PCGA-ND, was developed via Fe³⁺ and TEMPO catalyzed oxidative polymerization of chlorogenic acid. The resulting PCGA-NDs exhibited a uniform size of approximately 5 nm. Compared with conventional polyphenol-based materials, PCGA-NDs exhibited significantly enhanced resistance to spontaneous oxidation, retaining over 99% of their initial electrochemical activity and optical absorbance after 15 days of storage. A granzyme B responsive fluorescent probe was constructed by covalent conjugation of a quenched peptide substrate onto the PCGA-ND surface. Under near infrared irradiation, PCGA-NDs induced effective photothermal tumor ablation and immunogenic cell death in a 4T1 breast cancer model. Meanwhile, their quinone-catechol redox activity selectively scavenged excessive extracellular ROS from mitochondrial dysfunction after heat injury and preserved cytotoxic activities of T lymphocytes recruited and infiltrated after ICD. Granzyme B-responsive fluorescence enabled in situ quantification of cytotoxic T-cell activity with high spatiotemporal resolution, yielding a signal-to-background ratio exceeding 10-fold upon enzymatic activation, thereby providing immune feedback for photothermal dose adjustment. Collectively, the strategy resulted in a tumor growth inhibition rate of 99.42% relative to control treatments in 4T1 tumor-bearing mice, accompanied by a more than 13-fold increase in intratumoral CD8⁺ T - cell infiltration. Overall, this work establishes a generalizable theranostic framework that couples photothermal therapy with immune responsive imaging and redox regulation, providing a practical strategy for improving immune preservation and therapeutic precision in photo immunotherapy.