Tuning Exciton Coupling of Non-Conjugated Cyanine Dimers for Efficient Photodynamic Immunotherapy

Cyanine dyes usually serve as good fluorescence probes but not as efficient photosensitizers owing to the spin-forbidden intersystem crossing process and short excited-state lifetime. Nevertheless, the structure-derived energy release from the excited state could enable dyes to function efficiently. In this work, we developed cyanine dimers (2o-Cy, 2m-Cy, and 2p-Cy) based on exciton coupling effects by connecting two Cy5.5 molecules at the N-indole site with nonconjugated ortho/meta/para-bis(bromomethyl)benzene linkers. These dimers exhibited significantly enhanced molar extinction coefficients (32-45 × 10⁴ M cm^-1) as well as satisfactory triplet excited-state quantum yields (32-44%) and lifetimes (10.6-11.9 μs), leading to a substantially enhanced reactive oxygen species production along with efficient antitumor activity under both normoxic and hypoxic conditions. Furthermore, 2p-Cy NPs ablated primary tumors, inhibited distant tumor growth, and prevented metastatic regrowth via photoinduced innate immune activation. This dimer-based strategy represents a powerful approach to develop high-performance photosensitive dyes for antitumor photodynamic immunotherapy.