Design of Experiments (DoE)‐Optimized Polymeric Oxytocin Nanoparticles for Enhanced Nose‐to‐Brain Delivery

Abstract Oxytocin (OT) is a promising candidate for regulating social behavior in autism spectrum disorder (ASD). However, its inconsistent efficacy can be attributed to the lack of an efficient delivery system that selectively target the brain without inducing peripheral side effects following intranasal (IN) administration. In this study, OT is encapsulated within an FDA‐approved poly (lactic‐co‐glycolic acid) (PLGA) nanoparticles (OT‐NP) to improve nose‐to‐brain (NTB) delivery. A PEGylated version (OT‐NP‐PEG) is developed to improve nasal mucosal diffusion. Optimization using a design of experiments (DoE) approach produced nanoparticles with hydrodynamic diameters of ≈93–116 nm, polydispersity index ≈0.20, zeta potential –21 to –33 mV, and drug loading ≈2.8–3.5% (w/w). The stable OT‐NP‐PEG showed sustained release (>42% and 58% at 24 and 72 h) and greater diffusion through simulated nasal mucus. [ ¹⁴ C] OT is synthesized with chemical and radiochemical yields of 74% and 53%, respectively. Following IN administration in mice, [ ¹⁴ C] OT‐NP‐PEG demonstrated rapid brain uptake, particularly in the olfactory bulb and frontal cortex, with reduced blood and liver exposure compared with free [ ¹⁴ C] OT. Finally, IN OT‐NP‐PEG significantly increased self‐grooming frequency in mice, indicating maintained bioactivity and behavioral effects. Overall, OT‐NP‐PEG offers a rationally designed nanoplatform for brain‐targeted OT delivery in ASD and other neuropsychiatric disorders.