On the comparison between organic batch and aqueous microfluidic PEG-Jeffamine nanogels synthesis for sustained drug release

Nanogels represent an emerging class of soft nanomaterials capable of combining high water content, structural versatility, and tunable responsiveness, making them increasingly attractive for advanced drug delivery applications. Here, we present a modular and fully aqueous strategy to generate fluorescent PEG-Jeffamine nanogels through the integration of orthogonal click chemistry with a continuous-flow microfluidic platform. Unlike conventional emulsification-sonication-evaporation methods, which rely on poorly controlled mixing and often yield modest encapsulation efficiencies, the microfluidic approach provides a scalable and reproducible hydrodynamic environment that enables precise control over network formation, particle morphology, and in-line drug loading. Using FITC (hydrophobic) and RhB (hydrophilic) as model compounds, we demonstrate that the simultaneous synthesis-and-loading configuration (flow/flow) markedly enhances encapsulation efficiency and reduces early burst release compared with all batch-derived formulations. Specifically, the encapsulation efficiency increased from 54.2% to 84.9% for FITC and from 92.1% to 95.9% for RhB when moving from batch/batch to flow/flow processing. Structural and morphological analyses (DLS, Cryo-TEM) confirm the formation of monodisperse nanogels with controlled nanoscale dimensions (90-110 nm), while quantitative image analysis reveals a significantly higher particle circularity for flow-synthesized nanogels, indicating improved shape regularity. In addition, EDS analysis verifies the retention of reactive moieties that enable further post-synthetic functionalization. Overall, this work introduces a scalable and water-based microfluidic workflow for producing multifunctional PEG-Jeffamine nanogels with enhanced drug loading, sustained release, improved morphological uniformity, and reduced cytotoxicity, offering a promising platform for high-dose and long-term therapeutic applications.