Bridging hydrogen-bond-stabilized polymeric coacervate core micelles for high-efficiency drug encapsulation and delivery

Polymeric nanoparticles represent one of the most promising classes of non-lipid-based drug delivery vehicles. However, their clinical translation remains limited by poor drug loading capacity and suboptimal delivery efficiency. We here develop one type of polymeric nanoparticles, referred to as PCCMs (Polymeric Coacervate Core Micelles), which are assembled from a sulfoxide-containing block polymer. Hydrophobic drugs can be efficiently encapsulated into PCCMs via a fast, low-energy "Mix-and-Go" approach, reducing reliance on organic solvents and simplifying the drug-loading process. Moreover, PCCMs show high drug loading capacities and improved stability towards versatile hydrophobic drugs. Upon evaluating 40 different drugs, 45% of the tested compounds achieve drug loading contents exceeding 40%, 80% exceed 30%, and 100% surpass 20%. Both quantitative structure-property relationship (QSPR) calculations and experimental methods identify that hydration water within PCCMs' self-coacervated cores acts as the molecular barrier, substantially inhibiting long-range-ordered drug molecule packing and stabilizing drug aggregates at the nanoscale via bridging hydrogen bonds among the polymer-water-drug. Finally, we demonstrate that PCCMs exhibit significantly higher systemic delivery efficacy compared to commercial polymeric micelle formulations in female BALB/c mice. The high loading capacity, versatility, and efficacy of PCCMs pave the way for the clinical translation of polymeric nanoparticles.