A Type I Photosensitizer-Polymersome Boosts Reactive Oxygen Species Generation by Forcing H-Aggregation for Amplifying STING Immunotherapy.

Activation of the innate immune Stimulator of Interferon Genes (STING) pathway potentiates antitumor immunity. However, delivering STING agonists systemically to tumors presents a formidable challenge, and resistance to STING monotherapy has emerged in clinical trials with diminishing natural killer (NK) cell proliferation. Here, we encapsulated the STING agonist diABZI within polymersomes containing a Type I photosensitizer (NBS), creating a nanoagonist (PNBS/diABZI) for highly responsive tumor immunotherapy. This structure promoted H-aggregation and intersystem crossing of NBS, resulting in a ∼ 3-fold amplification in superoxide anion and singlet oxygen generation. The photodynamic therapy directly damaged hypoxia tumor cells and stimulated the proliferation of NK cells and cytotoxic T lymphocytes, thereby sensitizing STING immunotherapy. A single systemic intravenous administration of PNBS/diABZI eradicated orthotopic mammary tumors in murine models, achieving long-term antitumor immune memory to inhibit tumor recurrence and metastasis and significantly improving long-term tumor-free survival. This work provides a design rule for boosting reactive oxygen species production by promoting the intersystem crossing process, highlighting the potential of Type I photosensitizer-polymer vehicles for augmenting STING immunotherapy.