Kinetically stabilized nanocondensates via guided co-assembly: resolving solubility-potency mismatches and solvent confounding in drug discovery.

Abstract

Physicochemical and vehicle-derived artifacts, such as precipitation and solvent-driven perturbations, often decouple nominal dose from the bioavailable aqueous fraction, leading to distorted potency and mechanism assignments in preclinical assays. Here we introduce e-PASS, a computationally guided co-assembly strategy that prioritizes pharmaceutically relevant excipients and generates kinetically stabilized, drug-rich nanocondensates. These nanocondensates act as dynamic reservoirs that sustain free-compound availability during assay-relevant dilution and handling, thereby improving dosing fidelity and maintaining aqueous exposure, as quantified by AUC-based metrics relative to conventional dimethyl sulfoxide dilution. Across chemically diverse kinase and antifibrotic inhibitors, e-PASS suppresses precipitation artifacts, mitigates dimethyl sulfoxide-driven confounding, and yields concentration-response relationships that more faithfully reflect intrinsic compound activity, with mechanism-consistent responses. Improved chemical availability further translates into enhanced systemic exposure and therapeutic efficacy in tumor and liver-fibrosis models. Together, these results establish nanocondensate reservoirs as a general physicochemical lever to overcome precipitation- and vehicle-derived artifacts and expand screenable chemical space for reliable discovery workflows.

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