Heptamethine Cyanine Dyes with Ultra‐Efficient Excited‐State Nonradiative Decay for Synergistic Photothermal Immunotherapy

Abstract Organic dyes in the excited singlet state (S 1 ) decay via intersystem crossing (ISC) to the triplet state, radiative dissipation as fluorescence, or nonradiative decay for thermal deactivation. Although many studies are conducted to improve ISC and fluorescence efficiency, few have optimized S 1 decay via thermal deactivation, which is crucial for designing photothermal agents. A strategy for inhibiting radiative decay and ISC by introducing electron withdraw groups (EWGs) into the meso position of heptamethine cyanines (Cy7) is reported here, which allows S 1 energy decay via nonradiative relaxation. The decrease in the electron density of Cy7 caused by EWGs improved the photostability, which is important for biological applications because conventional cyanine dyes are easily photobleached. The EWG substitutes acted as efficient rotation groups with low‐energy barriers, narrowing the energy gap between S 1 and the ground state and considerably improving the photothermal conversion efficiency (PCE). The PCE of CF 3 cy with the strongest EWG is increased up to 83%. Liposome is used as a carrier to improve the biocompatibility and tumor retention of CF 3 cy, which is combined with the toll‐like receptor agonist resiquimod (R848) for synergistic photothermal immunotherapy against both primary and distant tumors and elicits a long‐lasting immunological memory effect.