Supramolecular Stability of Benzene-1,3,5-tricarboxamide Supramolecular Polymers in Biological Media: Beyond the Stability–Responsiveness Trade-off

[Image: see text] Supramolecular assemblies have been gaining attention in recent years in the field of drug delivery because of their unique formulation possibilities and adaptive behavior. Their non-covalent nature allows for their self-assembly formulation and responsiveness to stimuli, an appealing feature to trigger a therapeutic action with spatiotemporal control. However, facing in vivo conditions is very challenging for non-covalent structures. Dilution and proteins in blood can have a direct impact on self-assembly, destabilizing the supramolecules and leading to a premature and uncontrolled cargo release. To rationalize this behavior, we designed three monomers exhibiting distinct hydrophobic cores that self-assemble into photo-responsive fibers. We estimated their stability–responsiveness trade-off in vitro, finding two well-separated regimes. These are low-robustness regime, in which the system equilibrates quickly and responds readily to stimuli, and high-robustness regime, in which the system equilibrates slowly and is quite insensitive to stimuli. We probed the performance of both regimes in a complex environment using Förster resonance energy transfer (FRET). Interestingly, the stability–responsiveness trade-off defines perfectly the extent of disassembly caused by dilution but not the one caused by protein interaction. This identifies a disconnection between intrinsic supramolecular robustness and supramolecular stability in the biological environment, strongly influenced by the disassembly pathway upon protein interaction. These findings shed light on the key features to address for supramolecular stability in the biological environment.