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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\u00a0encapsulated within an FDA\u2010approved poly (lactic\u2010co\u2010glycolic acid) (PLGA) nanoparticles (OT\u2010NP) to improve nose\u2010to\u2010brain (NTB) delivery. A PEGylated version (OT\u2010NP\u2010PEG) is developed to improve nasal mucosal diffusion. Optimization using a design of experiments (DoE) approach produced nanoparticles with hydrodynamic diameters of \u224893\u2013116 nm, polydispersity index \u22480.20, zeta potential \u201321 to \u201333 mV, and drug loading \u22482.8\u20133.5% (w\/w). The stable OT\u2010NP\u2010PEG showed sustained release (&gt;42% and 58% at 24 and 72 h) and greater diffusion through simulated nasal mucus. [\n                    <jats:sup>14<\/jats:sup>\n                    C] OT is synthesized with chemical and radiochemical yields of 74% and 53%, respectively. Following IN administration in mice, [\n                    <jats:sup>14<\/jats:sup>\n                    C] OT\u2010NP\u2010PEG demonstrated rapid brain uptake, particularly in the olfactory bulb and frontal cortex, with reduced blood and liver exposure compared with free [\n                    <jats:sup>14<\/jats:sup>\n                    C] OT. Finally, IN OT\u2010NP\u2010PEG significantly increased self\u2010grooming frequency in mice, indicating maintained bioactivity and behavioral effects. Overall, OT\u2010NP\u2010PEG offers a rationally designed nanoplatform for brain\u2010targeted OT delivery in ASD and other neuropsychiatric disorders.\n                  <\/jats:p>","DOI":"10.1002\/smll.202511603","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T10:52:56Z","timestamp":1766141576000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Design of\u00a0Experiments (DoE)\u2010Optimized Polymeric Oxytocin Nanoparticles for Enhanced Nose\u2010to\u2010Brain Delivery"],"prefix":"10.1002","volume":"22","author":[{"given":"Naveed","family":"Ahmad","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  Franklin\u2010Wilkins Building, 150 Stamford Street London SE1 9NH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunping","family":"Han","sequence":"additional","affiliation":[{"name":"Institute of 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Neuroimaging, Institute of Psychiatry Psychology and Neuroscience King's College London  De Crespigny Park London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  Franklin\u2010Wilkins Building, 150 Stamford Street London SE1 9NH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0894-8424","authenticated-orcid":false,"given":"Marija M.","family":"Petrinovic","sequence":"additional","affiliation":[{"name":"Department of Forensic and Neurodevelopmental Sciences Institute of Psychiatry Psychology and Neuroscience King's College London  16 De Crespigny Park London SE5 8AF UK"},{"name":"Department of Neuroimaging, Institute of Psychiatry Psychology and Neuroscience King's College London  De Crespigny Park London SE5 8AF UK"},{"name":"Medical Research Council Centre for Neurodevelopmental 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