Phospholipid‐Drug Conjugates Self‐Organized into Well‐Defined Supramolecular Nanotubes for Efficient Drug Delivery

Controlled self-organization of amphiphilic phospholipid camptothecin (CPT) conjugates (named PCCs) selectively forms supramolecular nanotubes with varying lengths and polydispersity. Our study elucidates the underlying mechanisms governing PCC assembly, demonstrating that π-π stacking interactions derived from the planar, conjugated structure of CPT play a pivotal role in nanotube formation. Precise modulation of the hydrophobic characteristics of PCC linkers enables fine-tuning of π-stacking strength, thereby controlling the length of the nanotubes, ranging from the nano- to micro-scale. With exceptionally high drug-loading efficiencies (43.9% to 52.3%) and stimulus-responsive release properties, the optimized PCC nanotubes exhibit tumor-selective cytotoxicity of 20- to 50-fold greater potency against tumor cells compared to normal cells. Furthermore, PCC nanotubes of intermediate length (0.3-0.5 µm) display prolonged circulation times than conventional liposomes, resulting in enhanced tumor-targeting and therapeutic efficacy.