A Type I Photosensitizer-Polymersome\nBoosts Reactive\nOxygen Species Generation by Forcing H‑Aggregation for Amplifying\nSTING Immunotherapy

Activation of the innate immune Stimulator of Interferon\nGenes\n(STING) pathway potentiates antitumor immunity. However, delivering\nSTING agonists systemically to tumors presents a formidable challenge,\nand resistance to STING monotherapy has emerged in clinical trials\nwith diminishing natural killer (NK) cell proliferation. Here, we\nencapsulated the STING agonist diABZI within polymersomes containing\na Type I photosensitizer (NBS), creating a nanoagonist (PNBS/diABZI)\nfor highly responsive tumor immunotherapy. This structure promoted\nH-aggregation and intersystem crossing of NBS, resulting in a ∼\n3-fold amplification in superoxide anion and singlet oxygen generation.\nThe photodynamic therapy directly damaged hypoxia tumor cells and\nstimulated the proliferation of NK cells and cytotoxic T lymphocytes,\nthereby sensitizing STING immunotherapy. A single systemic intravenous\nadministration of PNBS/diABZI eradicated orthotopic mammary tumors\nin murine models, achieving long-term antitumor immune memory to inhibit\ntumor recurrence and metastasis and significantly improving long-term\ntumor-free survival. This work provides a design rule for boosting\nreactive oxygen species production by promoting the intersystem crossing\nprocess, highlighting the potential of Type I photosensitizer-polymer\nvehicles for augmenting STING immunotherapy.