Safety, Distribution, and Pharmacokinetics of Biodegradable P( <scp>AAm</scp> ‐co‐ <scp>MAA</scp> ) Nanogels Following Systemic Administration in Mice

Systematic analysis of the fate of hydrogel nanoparticles after in vivo administration is essential for their clinical translation. Biodegradable, disulfide-crosslinked synthetic nanogels are a promising platform for the delivery of therapeutic molecules, but their biodistribution and clearance profiles remain underexplored compared to other solid nanoparticles. In this study, we investigated the safety, pharmacokinetics, tissue, and cellular distribution profiles of poly(acrylamide-co-methacrylic acid) (P(AAm-co-MAA)) nanogels following a single intravenous or intraperitoneal injection. The nanogels exhibited rapid clearance from plasma, followed by early distribution primarily to the kidneys, liver, and small intestine. Within the liver, the nanogels showed preferential uptake by endothelial cells and resident macrophages. We further revealed organ-specific differences in nanogel retention and clearance, with highly perfused organs demonstrating parallel clearance behavior with plasma, while organs such as the kidneys and small intestine served as sites of longer nanogel retention. Single injections of P(AAm-co-MAA) nanogel suspension did not induce any systemic innate immune activation nor organ-specific toxicity, demonstrating a promising safety profile. These findings provide new insights into the in vivo behavior of redox-responsive nanogels and provide a framework for their rational design and clinical translation.