Droplet-Based Synthesis of Nanogels for Controlled Drug Delivery via Two Photon Polymerization-3D Printed Microfluidic Device

Nanogels (NGs) show great potential for innovative therapies due to their capability of reproposing the hydrogels features at the nanoscale. However, conventional batch syntheses exhibit shortcomings that bind the control over the reaction parameters and batch-to-batch reproducibility. Droplet-based microfluidics represents a valuable strategy to overcome these constraints, enabling precise manipulation of fluids/molecules to design nanoscaffolds. Standard microfluidic fabrication methods, such as soft lithography, hot-embossing or molding, require multistep process, and the successful fabrication depends on several factors, including the operator expertise. This work proposes two-photon polymerization (TPP) 3D printing as a straightforward method to produce a microfluidic device for droplet-based synthesis of NGs. The microfluidic platform enables controlled generation of microdroplets (150–80 µm, with size variation up to 47%), which work as microreactors, allowing modulation of NG dimensions (320–175 nm) and properties, while preserving an extremely low polydispersity (<0.1). NGs composed of polyallylamine and hyaluronic acid are synthesized and evaluated in vitro for cisplatin delivery in ovarian cancer cells. Compared to free drug administration, NG-mediated delivery enhances the therapeutic effect by ≈30% after 72 h. This highlights the potential of the nanomaterial in tumoral scenarios and proves the functionality of the TPP-printed microfluidic device in NG droplet-based synthesis.