Light-Driven Plasma Membrane-to-Nucleus Cascade Targeting Achieves Concurrent Pyroptosis and STING Activation.

Sequential targeting of the plasma membrane and nucleus holds great promise for concurrent pyroptosis and STING-mediated antitumor immunity, but achieving such cascade localization with a single molecular entity remains challenging, as existing strategies rely on multi-component carriers or endogenous stimuli with limited spatiotemporal precision. Here, we report the first example of a light-driven, carrier-free, plasma membrane-to-nucleus cascade-targeting photosensitizer (PMNu-4-NI) that operates through a single small molecule. Designed with a hydrophobic, planar naphthalimide unit and a dicationic triphenylamine pyridinium core, PMNu-4-NI initially anchors in the plasma membrane. Upon light irradiation, localized ROS generation disrupts membrane integrity, triggering pyroptosis via the caspase-1/GSDMD pathway, while simultaneously releasing the molecule from the membrane. The liberated photosensitizer then translocates into the nucleus, where the naphthalimide moiety intercalates into DNA and activates the cGAS-STING pathway. This dual, time-resolved action couples membrane-initiated pyroptosis with nuclear-initiated STING activation, producing a robust immunogenic cell death response. In a murine 4T1 breast tumor model, PMNu-4-NI achieves potent antitumor efficacy with negligible systemic toxicity. Furthermore, in vivo immune profiling reveals enhanced CD8+ T cell infiltration, a significant abscopal effect, and effective suppression of lung metastasis, collectively confirming systemic antitumor immune activation. This work establishes a design paradigm for photodynamic immunotherapy and a generalizable platform for next-generation photosensitizers with programmable spatiotemporal dynamics.