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Fulfilling such a goal via oral delivery can be conceivable owing to its expedience of self-medication and non-invasiveness. In this context, the oral behavioral trend was customized via tripolyphosphate cross-linked chitosan-based shell with lipid polymer hybrid core (TPP:CS-LPH) enclosing the antidepressant drug, mirtazapine (MIR). LPH nanoparticles were made of the PLGA core and the newly investigated lipid shell of lecithin and the pegylated lipid, Tefose 1500. Considering industrial scalability and applicability, spray drying was performed with thorough characterization. The impact of a cross-linked chitosan-based shell with LPH core on the in vivo pharmacokinetic behavior in brain and blood and pharmacodynamics in stressed mice (either daily regimen or every 3 days) was assessed and correlated to daily oral MIR suspension. The coated spray-dried nanocomposites were felicitously formed, exhibiting\u2009&gt; 95% MIR association efficiency, controlled pH-dependent MIR release, and physicochemically, structurally, and morphologically verified cross-linked CS coating. For the selected formula (SD\/TPP:CS-LPH\n                    <jats:sub>o<\/jats:sub>\n                    ), the cross-linked chitosan-based shell yielded a 39-fold increase in brain\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    and extended\n                    <jats:italic>t<\/jats:italic>\n                    <jats:sub>1\/2, brain<\/jats:sub>\n                    equivalent to 4.7 times compared to oral MIR suspension. The superior antidepressant efficacy of SD\/TPP:CS-LPH\n                    <jats:sub>o<\/jats:sub>\n                    , especially when administered every 3\u00a0days, was also accentuated in terms of considerable amelioration of behavioral response, decreased levels of brain biomarkers (brain-derived neurotrophic factor and serotonin), and histopathological findings. In conclusion, promising brain-directed oral delivery for MIR with improved bioavailability and therapeutic efficacy can be made possible by this tactic.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s12035-025-05403-5","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T04:19:00Z","timestamp":1765167540000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cross-linked Chitosan-Based Shell with Mirtazapine Lipid Polymer Hybrid Core as Integrated Spray-Dried Bionanocomposites for Boosted Brain-Directed Oral Delivery"],"prefix":"10.1007","volume":"63","author":[{"given":"Dalia M.","family":"Elbehairy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enas","family":"Elmowafy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rihab","family":"Osman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omaima A.","family":"Sammour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"issue":"1","key":"5403_CR1","first-page":"106","volume":"1","author":"M Al Gailani","year":"2022","unstructured":"Al Gailani M, Liu M, Wen J (2022) Ligands for oral delivery of peptides across the blood-brain-barrier. 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