A Multifunctional Near-Infrared Platinum(II) Agent for High-Performance Chemo-Photothermal Therapy.

Conventional platinum-based drugs are always constrained by their limited therapeutic efficacy due to sole chemotherapy without diagnostic guidance. This makes the development of multifunctional theranostic platinum complexes an appealing goal in medicinal chemistry. Herein, we designed a multifunctional bidentate platinum(II) complex, namely, BSeTPE-Pt-ac, featuring near-infrared (NIR) emission, an aggregation-induced emission (AIE) effect, and a photothermal effect, and achieved tumor-specific imaging and efficient gene-regulation synergized chemo-photothermal therapy (chemo-PTT). The introduction of 6/6 metallocycles linked to the benzoselenadiazole acceptor of the AIEgen expanded the electron conjugation effect, achieving NIR emission by leveraging a strong intramolecular metal-to-ligand charge transfer. The incorporation of benzoselenadiazole and tetraphenylethylene units modulated the photophysical property and increased molecular steric hindrance, endowing BSeTPE-Pt-ac with AIE and photothermal effects. To further optimize its therapeutic regimen, we executed a systematic bioinformatics-driven mapping to decode the cellular response to BSeTPE-Pt-ac, identifying thermal-resistance-related antiapoptotic gene B-cell lymphoma 2 (BCL2) as the key and direct intervention target. Synergistic gene regulation was introduced by co-delivering BCL2 antisense oligonucleotide and BSeTPE-Pt-ac with amphiphilic tumor-targeting polymers, which effectively silenced BCL2 expression, overcame thermal resistance, and thus maximized the chemo-PTT efficacy of BSeTPE-Pt-ac. Our work elucidates the rational design of a multifunctional platinum(II) agent by effectively integrating key anticancer functionalities, offering valuable insights into the development of advanced multifunctional agents.