Self‐Assembled Macrocyclic Nanocarriers for Rapid Ratiometric Loading and Dosing of Multidrug Combinations

Screening optimal drug combinations and dosing ratios is crucial for achieving and maximizing the synergistic therapeutic benefits in combined treatments. Traditional drug loading methods lack the precision to control drug ratios or involve complex technologies, failing to meet the demands of large-scale screening in accuracy, convenience, and applicability. To address this, we developed a thermodynamically programmable macrocyclic nanoplatform based on amphiphilic calixarenes that overcomes the kinetic limitations on drug loading accuracy and reproducibility. This platform achieved precise drug loading and release with convenient tunability and broad-spectrum applicability. For a series of drugs across various ratios, the actual loading ratio is > 95% consistent with the assigned values, and the consistency in delivery into cells and tumor tissues is also > 95%, enabling physicochemical control over the combination ratios. This work illustrates a feasible paradigm to screen for optimal drug ratios, providing a high-throughput approach for advancing combinatorial therapeutics.