Looking beyond the experimental settings, SHAP values for the most important features of models rdk5-LC40-RF (Figure ) and mordred-LE80-RF (Figure ) provide insight into structural elements and properties of formulations enabling ultrahigh drug loading. From the RDK5 fragments responsible for increasing the count of the relevant fingerprint bits (Figure ), it is evident that the rdk5-LC40-RF model predicts high LC values for mixtures containing large amounts of non-aromatic oxygen elements such as hydroxyl and ether groups, either situated adjacent to alkyl groups or directly bound to aromatic rings. Bit 9583 encodes for (alkylated) catechol groups present e.g. in curcumin, etoposide, diosmin and erlotinib, but also for lactone moieties in simvastatin and podophyllotoxin. Bits 13779 and 2610 count many different oxygen moieties, including a large quantity of hydroxyl groups as e.g. found in curcumin, paclitaxel, rutin and dasatinib. To smaller degrees, fingerprints also encompass aromatic nitrogens (e.g. bit 4612 for olanzapine) and sulfur atoms bound to aromatic rings. The latter includes sulfonyl groups as found in vismodegib and sulfonamides, e.g. present in celecoxib. Only the descripor DRU G_rdk5_11741 includes a mainly hydrophobic propyl fragment limited to drugs. A higher number of all these RDK5 fragments contributes to higher loading, as indicated by positive SHAP values. This suggests that the hydrophobic cargo should contain several polar elements, possibly for interactions with the amide groups of polymers. The amount of hydrogen bond forming functional groups, captured with the majority of these RDK fingerprints, has also been investigated as influential parameter in previous studies for a smaller selection of drugs. While Lim et al. discussed electronegative and hydrogen bond-accepting groups as polymer interaction strengthening factors for paclitaxel and vismodegib, the presence of tertiary amides within the polymers should favor interactions with donor groups, e.g. hydroxyl groups encoded with RDK5 bits 13779 and 2610. However, as we previously observed both experimentally and in silico , these micelles contain significant amounts of water. In principle, this can affect micelle morphology but also enable polymer-drug interactions with acceptor groups via bridging water molecules, as partly observed in our recent modeling study . As we also described for a smaller drug library , we could not detect a simple correlation of the number of hydrogen bond donors, acceptors or their ratio with LC or LE values for this extended database. While the probability of drugs with no donor or acceptor groups providing high LC values is low (Figure ), there are still exceptions. Drugs that can be solubilized with LC values above 30 % with no donor groups resemble aromatic molecules: schisandrin A , clotrimazole, mitotane and BT-44 . Overall, the relevant fingerprints suggest that hydrophobic guest molecules need to contain a sufficient amount of polar elements that could enhance loading through coordination of polymer amides, beyond more unspecific hydrophobic interactions.