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Premature Ejaculation (PE) has 4%\u201366% worldwide effects on self-esteem, relationships, and quality of life. Poor sexual confidence, anxiety, and sadness may worsen the issue. For this disease, dapoxetine HCl (DH) is used. In normal and streptozotocin (STZ)-induced diabetic rats, DH-loaded poly (lactic-co-glycolic acid) PLGA NP intranasal (IN) therapy was compared to standard lidocaine for DH release, entrapment efficiency, behavioural analysis, histopathological and immunohistochemistry expression, as neuroprotection inspection and proto-oncogene c-Fos (FOS) protein sequence expression. Also, in silico brain serotonin and FOS protein analyses were performed. Double-emulsion-solvent evaporation produced DH-loaded PLGA NP for IN quick-acting PE. Safe, controlled release, and effectiveness were investigated in PE rats using DH-PLGA NP. The brain\u2019s FOS protein expression, mount, intromission, post-ejaculatory, and Ejaculation frequencies were estimated. Optimized spherical NPs were 174\u00a0nm in size,\u2009\u2212\u200969.45\u00a0mV zeta potential, 98.04% entrapment efficiency, and 78.61% release after 8\u00a0h. The brain\u2019s ejaculation centre\u2019s rapid-acting DH prolongs intra-ejaculation, lowers FOS protein density, and normalizes hippocampus neurons. Histology and immunohistochemistry confirmed behavioural results of lower FOS protein expression and delayed ejaculation. Docking revealed that the DH ligand binds more strongly to brain protein active sites involved in premature ejaculation via rapid brain delivery bypassing the BBB via IN dosing, confirmed by behavioural analysis, histopathology, and immunohistochemistry. Using DH acutely decreased rapid ejaculation and changed contextual neuronal activity in ejaculatory network brain regions. Our results improve PE neurobiology and pharmacology research. Expression of FOS protein in DH nanoformula IN protects normal and diabetic rats in normal and diabetic premature ejaculated rats.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-04876-4","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T02:33:33Z","timestamp":1766457213000},"page":"8131-8154","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nose to brain delivery of dapoxetine-loaded PLGA nanoparticle for treatment of premature ejaculation distress in normal and diabetic rats with in silico targeting brain FOX and serotonin proteins"],"prefix":"10.1007","volume":"399","author":[{"given":"Fatma I. 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