Design of Asymmetric Particles Containing a Charged Interior and a Neutral Surface Charge: Comparative Study on <i>in Vivo</i> Circulation of Polyelectrolyte Microgels

Lowering the modulus of hydrogel particles could enable them to bypass <i>in vivo</i> physical barriers that would otherwise filter particles with similar size but higher modulus. Incorporation of electrolyte moieties into the polymer network of hydrogel particles to increase the swelling ratio is a straightforward and quite efficient way to decrease the modulus. In addition, charged groups in hydrogel particles can also help secure cargoes. However, the distribution of charged groups on the surface of a particle can accelerate the clearance of particles. Herein, we developed a method to synthesize highly swollen microgels of precise size with near-neutral surface charge while retaining interior charged groups. A strategy was employed to enable a particle to be highly cross-linked with very small mesh size, and subsequently PEGylated to quench the exterior amines only without affecting the internal amines. Acidic degradation of the cross-linker allows for swelling of the particles to microgels with a desired size and deformability. The microgels fabricated demonstrated extended circulation <i>in vivo</i> compared to their counterparts with a charged surface, and could potentially be utilized in <i>in vivo</i> applications including as oxygen carriers or nucleic acid scavengers