Reprogramming Aromatic Camptothecins into TOP1 Degraders via Synergistic Hydrophobic Tagging and Supramolecular Assembly.

Aromatic camptothecins (CPTs) are clinically potent TOP1 inhibitors constrained by an "aromaticity-solubility" paradox, which leads to poor bioavailability and efflux-mediated resistance. Here, we report a modular strategy to reprogram the planar CPT scaffold into multifunctional topoisomerase I (TOP1) degraders by integrating hydrophobic tagging (HyT) with supramolecular self-assembly. Adamantane HyT introduces an orthogonal aliphatic module, converting classical inhibitors into proteasome-dependent degraders with enhanced membrane permeability while preserving TOP1-DNA binding affinity. This tag synergistically acts as a supramolecular anchor, enabling host-guest assembly with poly(β-cyclodextrin) to form stable, pH-responsive nanoparticles without pharmacophore modification. Our lead candidate, SN-38-A2, demonstrates potent TOP1 degradation and achieves superior tumor regression in xenograft models compared to clinical irinotecan. This synergistic HyT-supramolecular approach rebalances aromaticity for optimized drug-like properties, establishing a paradigm to transform solubility-limited warheads into high-performance degraders with integrated delivery.