Perilipin‐2‐Anchored Lipid Droplet‐Targeting Phototheranostics

ABSTRACT Conventional photothermal agents are readily taken up by normal cells, which may cause off‐target damage. Lipid droplet (LD) targeting can enable photothermal agents to accumulate in tumor cells enriched in LDs, a central hub for lipid storage. We herein report an LD‐targeted theranostic agent , C‐BDP‐OMe, through a dual‐anchoring strategy that combines the principle of “like dissolves like” with specific docking to the PLIN2 protein. Structurally, C‐BDP‐OMe features an extended conjugated system and an asymmetric coumarin‐fused BODIPY scaffold, enabling NIR‐region optical properties, a large Stokes shift, and high photostability. The probe exhibits polarity‐sensitive behavior, with turn‐on fluorescence and a high signal‐to‐noise ratio under no‐wash conditions. Furthermore, C‐BDP‐OMe demonstrates robust photothermal performance, with a photothermal conversion efficiency of 62.6%, enabling localized photothermal ablation and resulting in effective tumor suppression while avoiding systemic side effects. The therapeutic mechanism was systematically investigated and shown to involve the concurrent activation of two distinct cell death pathways—apoptosis and ferroptosis. This work highlights the therapeutic value of subcellular organelle‐level precision interventions and underscores the importance of exploiting subtle microenvironmental features in the design of next‐generation anticancer theranostic agents.