Engineering Polymer-Protein Interactions to Control the Polymersome Protein Corona

Self-assembled polymersomes are nano-sized vesicles capable of encapsulating, protecting, and co-delivering hydrophobic and hydrophilic drugs. Their stable hydrophobic membranes and large hydrophilic cores make them strong candidates for the delivery of many biologic therapeutics, including RNAs, proteins, and plasmids. With amphiphilic block copolymers roughly between 25 and 45%, the lowest Gibbs free energy state is spherical. Though spherical polymersomes are effective, early studies suggest that non-spherical structures may enhance the specificity of delivery and uptake due to similarity to endogenous uptake targets. Using osmotic pressure, introduced through osmotic salts, we were able to elongate polymersomes made from polyethylene glycol-b-polylactic acid (PEG-b-PLA) while maintaining their membrane-bound structure, enabling enhanced co-delivery of hydrophilic and hydrophobic drugs in SHSY5Y neuroblastoma cells. While we believe that shape changes impacted intracellular uptake, we also know that salt can alter PEG conformation and structure. By altering PEG, these salts also impact the polymersome protein corona. Therefore, we investigated the impact of different Hofmeister series chaotropic salts on the biomolecular identity of PEG-b-PLA polymersomes after incubation in serum. Incubation with divalent salt ions, in particular, changed the size and surface chemistry of PEG-b-PLA polymersomes, leading to alterations in the specific protein composition of the corona. These differences appear to be driven by charge-based and biology-based interactions. All in all, this knowledge could be leveraged to engineer nanoparticles with tailored protein coronas.