Polymorphism control in crystalline clofazimine enables accelerated clinical translation of NIR-II phototheranostics

Clinically translatable fluorescent tracers with the second near-infrared (NIR-II, 1000–1700 nm) emission hold significant promise in bioimaging and phototherapy. Herein, we report on clofazimine (CFZ), a clinical organic drug, as a biocompatible and ultrasmall NIR-II aggregation-induced emission luminogen (AIEgen) for multimodal phototheranostics compared to traditional large emitters structures (exceeding 500 Da) containing extended π -conjugation and long alkyl side chains. This molecule selectively self-assembles into two types of crystalline aggregates in diverse polar solvents, exhibiting distinct photophysical characteristics in the NIR-II window. Polymorph- e with reversely eclipsed stacking simultaneously achieves through-space conjugation of the backbone and molecular motions, endowing it with superior NIR-II emission and photothermal properties compared to polymorph- s . Accordingly, nanoparticles of polymorph- e ( e -CFZ NPs) were applied to NIR-II fluorescence/photoacoustic/photothermal trimodal imaging-guided photothermal therapy against breast cancer. This enables clofazimine to be one of the smallest NIR-II emitters with multifunctional phototheranostic characteristics and excellent biocompatibility known to date, underscoring elaborately manipulating the aggregation of small-molecular drugs as a potential approach to accelerate clinical translation of NIR-II phototheranostics. Polymorphic regulation of the clinical drug clofazimine creates an ultrasmall NIR-II phototheranostic agent, demonstrating effective multimodal imaging-guided therapy against breast cancer with high biocompatibility.