{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:06:59Z","timestamp":1789189619739,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82505030"],"award-info":[{"award-number":["82505030"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82608800"],"award-info":[{"award-number":["82608800"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82505030"],"award-info":[{"award-number":["82505030"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82608800"],"award-info":[{"award-number":["82608800"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Technological Research Projects of Henan Province","award":["252102310476"],"award-info":[{"award-number":["252102310476"]}]},{"name":"Key Scientific Research Projects of Henan Provincial Higher Education Institutions","award":["25A360009"],"award-info":[{"award-number":["25A360009"]}]},{"DOI":"10.13039\/501100004761","name":"Henan Provincial Natural Science Foundation","doi-asserted-by":"crossref","award":["252300423794"],"award-info":[{"award-number":["252300423794"]}],"id":[{"id":"10.13039\/501100004761","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Henan Provincial Outstanding Youth Science Foundation","award":["252300421028"],"award-info":[{"award-number":["252300421028"]}]},{"name":"Henan Provincial Key Research and Development Special Program","award":["241111311500"],"award-info":[{"award-number":["241111311500"]}]},{"name":"Program for Innovative Research Team (in Science and Technology) in University of Henan Province","award":["26IRTSTHN018"],"award-info":[{"award-number":["26IRTSTHN018"]}]},{"name":"Henan Provincial Science and Technology Research and Development Program Joint Fund (Advantageous Discipline Cultivation Category) Project","award":["242301420021"],"award-info":[{"award-number":["242301420021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Objective: To develop a lactoferrin-modified sodium alginate nanogel loaded with saikosaponin A (SA-Lf-NG@SAA) and evaluate its potential antidepressant-like effects following intranasal administration. Methods: SA-Lf-NG@SAA nanogels were prepared and optimized using single-factor experiments combined with response surface methodology. The optimized formulation was characterized in terms of particle size, zeta potential, stability, morphology, drug-loading performance, and in vitro release behavior. Male C57BL\/6J mice were used to establish a chronic unpredictable mild stress (CUMS) model to evaluate the antidepressant-like effects of SA-Lf-NG@SAA after intranasal administration. Histopathological changes in the hippocampus and striatum were observed by hematoxylin and eosin staining. Western blotting was used to detect the expression of OLFM-1, OLFM-3, and OLFM-4 in olfactory bulb tissues, and immunofluorescence staining was performed to further examine their expression in the hippocampus and striatum. Results: The optimized SA-Lf-NG@SAA nanogels had an average particle size of approximately 85 nm and a zeta potential ranging from 0 mV to \u221210 mV, and they maintained their basic particle characteristics during a 14-day short-term physical stability study after dispersion in PBS. In vitro release analysis showed that SA-Lf-NG@SAA exhibited a distinct initial lag phase, followed by sustained drug release, with a cumulative release rate of approximately 75% at 72 h. Kinetic fitting using zero-order, first-order, Higuchi, and Korsmeyer\u2013Peppas models showed that the post-lag release profile was best described by the Higuchi model, suggesting a prolonged release pattern under the present in vitro conditions. In CUMS mice, intranasal administration of SA-Lf-NG@SAA effectively improved depression-like behaviors, alleviated pathological damage in the hippocampus and striatum, and enhanced neuronal morphology. Western blotting showed that SA-Lf-NG@SAA increased the expression of OLFM-1, OLFM-3, and OLFM-4 in olfactory bulb tissues. Immunofluorescence staining further confirmed that the expression of these proteins was significantly enhanced in the hippocampus and striatum, especially in the high-dose SA-Lf-NG@SAA group. Conclusions: SA-Lf-NG@SAA nanogels were successfully developed as a potential nanogel-based formulation intranasal administration of saikosaponin A, showing favorable physicochemical properties, short-term stability, and prolonged release behavior. Intranasal administration of SA-Lf-NG@SAA alleviated depression-like behaviors in CUMS mice and improved histopathological alterations in the hippocampus and striatum. The antidepressant-like effects of SA-Lf-NG@SAA may be associated with the regulation of OLFM-family protein expression in depression-related brain regions. These findings suggest that SA-Lf-NG@SAA has potential as a nanogel-based intranasal formulation for the delivery of active components from traditional Chinese medicine in depression therapy. However, the specific contribution of lactoferrin modification requires further validation using unmodified SA-NG@SAA as a control.<\/jats:p>","DOI":"10.3390\/ph19091425","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:02:48Z","timestamp":1788962568000},"page":"1425","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antidepressant Effects of Lactoferrin-Modified Sodium Alginate-Based Saikosaponin A Nanogels via Intranasal Administration: Involvement of Olfactomedin-Family Proteins"],"prefix":"10.3390","volume":"19","author":[{"given":"Jinbang","family":"Li","sequence":"first","affiliation":[{"name":"National International Cooperation Base of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"},{"name":"Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Han","sequence":"additional","affiliation":[{"name":"National International Cooperation Base of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"},{"name":"Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5414-3734","authenticated-orcid":false,"given":"Lihua","family":"Cao","sequence":"additional","affiliation":[{"name":"National International Cooperation Base of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Tian","sequence":"additional","affiliation":[{"name":"National International Cooperation Base of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyun","family":"Liu","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Li","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Li","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2999-805X","authenticated-orcid":false,"given":"Mingsan","family":"Miao","sequence":"additional","affiliation":[{"name":"National International Cooperation Base of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Kang","sequence":"additional","affiliation":[{"name":"National International Cooperation Base of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"},{"name":"Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.neuroscience.2015.05.053","article-title":"Pathogenesis of depression: Insights from human and rodent studies","volume":"321","author":"Hodes","year":"2016","journal-title":"Neuroscience"},{"key":"ref_2","first-page":"197","article-title":"Research progress on antidepressant Bupleurum prescriptions and saikosaponins","volume":"25","author":"Cao","year":"2023","journal-title":"J. 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