Strengthening D-A Push–Pull Interactions in BODIPY to Enhance Near-Infrared Absorption and Photothermal Conversion for Low-Intensity Photothermal Antitumor Therapy

Conventional photothermal therapy often relies on high-intensity laser excitation due to the limited photothermal conversion efficiency (PCE) of existing photothermal agents (PTAs), which compromises treatment safety and restricts clinical translation. To address this limitation, we designed and synthesized a series of boron-dipyrromethene (BODIPY)-based derivatives (BDP 1–4) featuring gradient-enhanced donor–acceptor (D-A) push–pull electronic effects for efficient photothermal antitumor therapy. The structure–activity relationships were systematically elucidated through photophysical characterization and in vitro/in vivo photobiological evaluation. From BDP 1 to BDP 4, the progressively strengthened push–pull effect leads to enhanced intramolecular charge transfer (ICT), which, in turn, results in a narrowed HOMO-LUMO gap, redshifted absorption into the near-infrared (NIR) region (up to 843 nm), markedly attenuated fluorescence emission, and a remarkable increase in PCE up to 88.3%. To improve water dispersibility and tumor targeting, these molecules were further encapsulated into nanoparticles using DSPE-PEG2000, and the nanoformulations retained high PCE. Both in vitro and in vivo studies demonstrated that under low-power laser irradiation (0.5 W·cm−2, 808 nm), the nanoformulation of BDP 4, which exhibited the highest PCE among the series, achieved pronounced photothermal tumor ablation without inducing systemic toxicity. Overall, this study proposes a molecular design strategy that synergistically modulates NIR absorption and photothermal conversion by enhancing the D-A push–pull effect. This strategy provides a design rationale for developing efficient, low-toxicity organic PTAs, and demonstrates potential applicability in low-power PTT modalities.