Harnessing Nanoreactors with Coupled Optical and Molecular Modalities for Photoenzymatic Modulation of Active Species in Cancer Photo-Immunotherapy.

The dynamic process in tumor ablation requires both the generation of reactive oxygen species (ROS) to elicit immunogenic cell death (ICD) and the subsequent reduction of ROS levels to maintain the stimulatory activity of signaling proteins and recover T cells' immune function. Inspired by the regulation mechanism of redox homeostasis in myeloid-derived suppressor cells and the high-selectivity in alcohols/aldehydes conversions of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and Fe(III) synergistic catalysis, photoenzymatic modulators with contradictory but synergistic functions are developed for adaptive photo-immunotherapy of cancer. In particular, poly(caffeic acid) (PCA) nanospheres are synthesized by highly efficient oxidative polymerization of CA. The obtained π-conjugated structures have an extended absorbance in the near-infrared (NIR) region, narrow band energy (0.86 eV), and low exciton binding energy (43.56 meV) that lead to polymerization-enhanced type I photosensitization and photostability. Meanwhile, abundant semiquinone radicals existing in PCA bestow them with superior antioxidant function. Under NIR irradiation, the elevated superoxide radical yields (3.5-fold compared with CA) and heat stress elicit robust ICD. When irradiation ceases, active species downregulation and the infiltration of T lymphocytes increase by 2.7-fold compared with conventional photosensitizers. As envisaged, this work demonstrates a novel tactic to remodel redox and immune homeostasis for effective inhibition of tumor growth and metastasis.