Blending Carbohydrate and Quinine-Based Polymers Imparts Colloidal Stability, Improved Performance, and Cell Specificity for mRNA Delivery

Quinine-based polymers have shown promise for effective delivery of nucleic acids; however, quinine's hydrophobicity has often resulted in uncontrolled aggregation (>1000 nm) of complexes. PEGylation is often used to improve the colloidal stability of nucleic acid delivery vehicles; however, this frequently results in reduced cellular internalization. Herein, we describe the synthesis of two diblock quinine polymers that utilize the carbohydrates glucose and galactose in place of PEG as the neutral hydrophilic block to deliver mRNA. These diblock stabilizers were blended with five hydrophobic quinine polymers at several mixing ratios to generate a library of 73 formulations, 47 of which produced submicron particles. The biophysical properties, such as particle size and mRNA binding, can be tuned by varying the mixture components and ratio. Our results show that the next generation, sugar-containing stabilizers outperformed PEGylated analogs, promoting greater cellular internalization, improved transfection, and potential for cell specificity.