Injectable Nanogel Jams for Affinity-Free nm Scale Molecular Diffusion Barriers

Localized delivery of small molecules and peptides is limited by rapid diffusion through swollen hydrogels. Increasing polymer concentration or crosslink density can reduce mesh size, but it also increases viscosity and injection force. Here, we address this trade-off by designing the matrix as a densely packed particle system rather than a continuous polymer network. PEG core-brush nanogels with a DLS hydrodynamic diameter of approximately 15 nm were prepared from PEG. Upon concentration, the nanogels formed a jammed colloidal assembly through particle contact and brush crowding. The PEG corona stabilizes and lubricates particles at low density, whereas at high density it generates steric contacts that slow rearrangement and produce solid-like behavior. Thus, molecular transport is governed by the short interparticle length scale of packed nanoscale particles, without requiring an ordered structure.

FRAP measurements with a 1260 Da hydrophilic probe showed that nanogel jamming markedly decreased the apparent diffusion coefficient without drug-matrix affinity. To stabilize the assembly and reduce the effective interparticle mesh, 3-arm PEG-thiol was introduced as a post-locking agent. Compared with the raw jammed assembly, the post-locked nanogel system further suppressed probe diffusion, resisted swelling or dispersion in free water, and preserved injectability in needle force tests. This study establishes 15 nm nanogel jamming and interparticle mesh locking as an affinity-free strategy for injectable local depots of molecular-scale therapeutics.