Biomimetic Self-Augmenting Photoimmuno-Nanoagonist Synergizing with cGAS-STING Pathway Activation for Enhanced Tumor...

Photoimmunotherapy is limited by inadequate dendritic cells (DCs) antigen presentation and cytotoxic T lymphocytes (CTLs) dysfunction. Innate immune activation can potentiate DCs maturation and restore CTLs function, augmenting photoimmunotherapy efficiency. Herein, we developed a biomimetic gold nanorod-core/mesoporous manganese dioxide (MnO₂)-shell nanoagonist (denoted as m@AMCR) loaded with chlorin e6 and rapamycin (Rap) to synergize photodynamic therapy (PDT)/photothermal therapy (PTT) with cGAS-STING pathway activation for enhanced tumor treatment. Tumor cell membrane biomimetic camouflage conferred m@AMCR with self-targeting ability toward homologous cancer cells. Subsequently, intratumoral glutathione triggered MnO₂ decomposition to release Rap. Rap augmented PDT/PTT by suppressing hypoxia-inducible factor-1α and heat shock protein 70 expression while downregulating matrix metalloproteinase-2 to inhibit tumor metastasis. Concurrently, the released Mn²⁺ activated the cGAS-STING pathway, promoting DCs maturation and CTLs infiltration. Finally, the combination of photoimmunotherapy-induced immunogenic cell death and cGAS-STING activation potently suppressed primary tumor growth and lung metastases. Overall, this biomimetic self-augmenting nanoagonist established a paradigm for tumor immunotherapy by integrating photoimmunotherapy with cGAS-STING-mediated innate immune activation.