Regulating Triplet Energy Level and Intramolecular Motion: An Aggregation-Induced Emission BODIPY for Near-Infrared Type I Photodynamic/Photothermal Synergistic Therapy

The combination of photodynamic therapy (PDT) and photothermal therapy (PTT) holds considerable promise for cancer treatment, but conventional Type II PDT is strongly limited by tumor hypoxia. Here, we designed a D-π-A-π-D BODIPY-based near-infrared aggregation-induced emission (AIE) photosensitizer, TBSN, by integrating tetraphenylethylene units and a rotatable N,N-diethylaniline moiety. Theoretical calculations identified S1 → T2 as the predominant intersystem crossing pathway and showed that the N,N-diethylaniline unit participated in the electronic redistribution of the T2 state. The calculated T1 → S0 energy of 0.42 eV made the energy-transfer process required for singlet-oxygen sensitization thermodynamically unfavorable. Electron paramagnetic resonance (EPR) spin-trapping experiments detected light-induced superoxide radical anions (O2·-) and hydroxyl radicals (·OH), but no discernible singlet oxygen (1O2) signal, supporting predominantly Type I reactive oxygen species (ROS) generation. Molecular dynamics simulations further showed that the molecular rotor retained considerable rotational freedom after aggregation, consistent with the photothermal conversion efficiency of 54.44%. After encapsulation with DSPE-PEG2000, TBSN@PEG retained pronounced ROS-generating and photothermal activities and exhibited effective photocytotoxicity under both normoxic and hypoxic conditions. Following intratumoral administration and 730 nm irradiation, TBSN@PEG produced localized heating and markedly inhibited 4T1 tumor growth, while showing favorable preliminary short-term biosafety at the tested dose. These results demonstrate a molecular design strategy that jointly regulates triplet-state electronic structure and residual rotor motion to balance Type I ROS generation and photothermal conversion.