Highly Stable, Ultrasmall Polymer-Grafted Nanobins (usPGNs) with Stimuli-Responsive Capability

Highly stable and stimuli/pH-responsive ultrasmall polymer-grafted nanobins (usPGNs) have been developed by grafting a small amount (10 mol %) of short (4.3 kDa) cholesterol-terminated poly(acrylic acid) (Chol-PAA) into an ultrasmall unilamellar vesicle (uSUV). The usPGNs are stable against fusion and aggregation over several weeks, exhibiting over 10-fold enhanced cargo retention in biologically relevant media at pH 7.4 in comparison with the parent uSUV template. Coarse-grained molecular dynamics (CGMD) simulations confirm that the presence of the cholesterol moiety can greatly stabilize the lipid bilayer. They also show extended PAA chain conformations that can be interpreted as causing repulsion between colloidal particles, thus stabilizing them against fusion. Notably, CGMD predicted a clustering of the Chol-PAA chains on the lipid bilayer under acidic conditions due to intra- and interchain hydrogen bonding, leading to the destabilization of local membrane areas. This explains the experimental observation that usPGNs can be triggered to release a significant amount of cargo upon acidification to pH 5. These developments put the lipid-bilayer-embedded Chol-PAA in stark contrast with traditional poly(acrylic acid) systems where the molar mass (M_n) of the polymer chains must exceed 16.5 kDa to achieve stimuli-responsive changes in conformation. They also distinguish the small usPGNs from the much-larger polymer-caged nanobin platform where the Chol-PAA chains must be covalently cross-linked to engender stimuli-responsive behaviors.