Rational Design of Probenecid‐Functionalized Silicon Phthalocyanine J‐Aggregated Nanoshuttles for Lipid Droplet‐Targeted Drug‐Resistant Theranostics

Probenecid, a clinical uricosuric agent with emerging therapeutic potential via membrane protein modulation, is covalently integrated with piperazine silicon phthalocyanine to construct a multifunctional theranostics, propanesulfonylpiperazine silicon phthalocyanine (PP-SiPc), for precise photodynamic therapy (PDT). Through intermolecular π-π stacking, polar interactions, and hydrophobic effects, PP-SiPc self-assembled into J-aggregated nanoshuttles (N-PP-SiPc) that exhibit enhanced UV/Vis absorption, intensified fluorescence, and superior photostability compared to the free form of PP-SiPc. N-PP-SiPc demonstrates high specificity for lipid droplets (LDs), enabling dynamic tracking and discrimination between lysosomal and non-lysosomal LDs-a critical capability for identifying drug-induced lipidosis associated with abnormal accumulation of non-lysosomal LDs. Furthermore, N-PP-SiPc exhibits rapid cellular internalization, improved targeting of LDs, and enhanced light-triggered reactive oxygen species (ROS) generation. These properties collectively contributed to potent PDT efficacy against both cancer cells and drug-resistant strains, underscoring its potential as a theranostic platform capable of overcoming resistance mechanisms. This work establishes a blueprint for developing transporter-modulated theranostic nanomaterials offering organelle-level diagnostic precision.