Macromolecular crowding is an organizing principle in soft matter and biological systems where high concentrations of macromolecules generate depletion forces that drive collective processes such as compaction, self-assembly, and phase separation. While the classical Asakura-Oosawa (AO) theory has been widely used to describe depletion interactions, it neglects crowder-crowder interactions and is unable to account for enhanced depletion observed in systems with attractive crowders. Here, we investigate the depletion potential of colloids immersed in Lennard-Jones crowders, which at modest crowder-crowder attraction form transient, correlated clusters, enhancing and extending the depletion range beyond classical AO predictions. We develop a cluster AO theory which treats clusters as effectively larger depletants, incorporating contributions from individual crowders and interactions between clusters. The resulting theoretical predictions mimic those obtained from umbrella sampling simulations, outperforming the predictions of classical AO theory, static polydisperse models, and traditional liquid-state-like superposition approximations without requiring costly sampling of colloid-crowder systems. Our findings highlight that prior knowledge of emergent cluster statistics suffices to predict depletion interactions in systems with interacting crowders, offering a tractable route to study crowding behavior in complex fluids.

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• Depletion interactions
• Colloids
• Molecular dynamics