Hypoxia-Tolerant Supramolecular Nanomicelles for Pyroptosis-Enhanced NIR-II Phototheranostics.

Abstract

Tumor hypoxia, limited solid-tumor imaging, and insufficient systemic antitumor immunity remain major challenges to effective cancer phototheranostics. Here, a molecular conformation engineering strategy is developed to construct TBBP, which features a strengthened electron donor, a moderately twisted conformation, extended π-conjugation, and a robust molecular skeleton free of labile olefinic π-bridges. TBBP exhibits excellent photostability, broadband second near-infrared (1000-1600 nm) emission, and efficient photothermal conversion (42.17%). Supramolecular assembly with DSPE-PEG2000 affords stable TBBP nanomicelles, TBBP NPs, that selectively generate superoxide radicals (O2 -•) and retain potent Type I photodynamic therapy (PDT) activity under hypoxia. Photoactivated TBBP NPs further induce mitochondrial dysfunction and caspase-3/GSDME-mediated immunogenic pyroptosis, promoting dendritic cell maturation and CD8+ T cell infiltration. In a bilateral 4T1 tumor model, TBBP NPs enable high-contrast second near-infrared (NIR-II) imaging, while synergistic Type I PDT and photothermal therapy elicit systemic antitumor immunity, achieving 92.0% primary tumor inhibition and 47.7% distant tumor inhibition. This work establishes a molecular conformation engineering strategy and extends its functionality through supramolecular assembly, synergistically integrating NIR-II imaging, hypoxia-tolerant Type I phototherapy, and photoimmunotherapy, thereby providing a generalizable molecular design principle for the development of next-generation multifunctional organic phototheranostic agents.