Significance Critical micellization concentration (CMC) is an important design consideration for developing all supramolecular biomaterials, and in particular for drug delivery systems. Once placed in an in vivo setting, supramolecular materials will start to dissociate into monomeric units, providing a means for therapeutic release and an essential pathway for clearance. This beneficial phenomenon could also lead to premature drug release and degradation. Through the design of a series of self-assembling prodrugs (SAPDs) of various CMCs, we developed a fundamental understanding of the role of CMC in therapeutic efficacy of supramolecular polymers. We found that the two important parameters of assessing a drug potential (efficacy and toxicity) can be correlated to the SAPD’s supramolecular form and monomeric form, respectively.