In this work, we have integrated molecular-scale computer simulations and unsupervised machine learning techniques to demonstrate that therapeutic peptide solubilization by a polymeric NP depends not solely on the overall NP structure but also on the specific conformations adopted by individual polymers within it. These distinct conformations impart different local chemical environments that regulate drug encapsulation. We previously demonstrated that polymer topology controls the ability of polymers to adopt specific conformations within NPs upon their self-assembly. Together, these results suggest that location-specific solubilization of drugs may be achieved by considering polymer topology and the resultant distribution of conformational states within self-assembled NPs.