Synergistic Phototherapy Using Zwitterionic Crystalline Nanoaggregates of Orthogonal Donor–Acceptor Small‐Molecule Dyads

Abstract Developing nanophotosensitizer (nanoPS) for synergistic phototherapy by leveraging the aggregation of small‐molecule dyes is compelling frontier in precision medicine, but challenges remain due to the limited understanding of the interactions between molecular structure, assembly behavior, and theranostic function. Here, the concept of “spin‐orbit charge‐transfer intersystem crossing (SOCT‐ISC) in crystalline aggregates” is introduced, which significantly enhances photodynamic (PD) and photothermal (PT) properties of small‐molecule‐based nanoPS. Specifically, a cationic pyridine (Py) group is incorporated at the meso ‐position of a tricyanofuran (TCF)‐containing anionic heptamethine cyanine (TCF‐Cy7‐TCF) dye to construct an orthogonal charge‐transfer dyad (TCF‐Cy7(Py)‐TCF), boosting triplet state formation through SOCT‐ISC mechanism to enhance the PD properties. Remarkably, the zwitterion moieties impart TCF‐Cy7(Py)‐TCF with high crystallinity even at ultralow concentrations, dictating its stacking behavior within aggregates and enhancing both PT and PD properties. The TCF‐Cy7(Py)‐TCF nanoaggregates exhibit superior singlet oxygen quantum yield (0.8% vs 0.2%) and photothermal conversion efficiency (55.06% vs 7.78%) compared to TCF‐Cy7‐TCF. Impressively, TCF‐Cy7(Py)‐TCF preferentially accumulates at tumor sites, yielding high signal‐to‐background ratios for tumor imaging in NIR‐I and NIR‐II windows, with minimal nonspecific binding. Finally, in vivo experiments confirm TCF‐Cy7(Py)‐TCF nanoaggregates function as nanoPS for synergistic phototherapy, offering a simple yet effective strategy to design single‐component PS for clinical translation.