The treatment of brain disorders via nose-to-brain delivery (NtBD) is a promising non-invasive strategy to bypass the blood-brain barrier. In this study, we developed and characterized polymeric nanoparticles (NPs) based on polylactic acid (PLA) and poloxamers (P188 and P407), synthesized via one-step or two-step nanoprecipitation methods. All formulations resultet in homogeneous, negatively charged NPs with a diameter of 110 nm, compatible with efficient brain delivery. Dissipative particle dynamics simulations confirmed the structural organization of NPs and highlighted the role of poloxamer in forming a hydrophilic surface. NPs modified with poloxamer demonstrated improved colloidal stability in artificial mucus and cerebrospinal fluid, unlike bare PLA NPs. In vitro assays on human nasal epithelial cells and differentiated neuronal cells showed no cytotoxicity. In vivo fluorescence imaging and immunostaining revealed the presence of NPs in the olfactory bulb as early as 1 hour post-administration. These results support NP-PLA-P188 as a promising formulation for effective and safe NtBD of drugs targeting neurological diseases.
