{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T04:21:41Z","timestamp":1773807701925,"version":"3.50.1"},"reference-count":43,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Exp Pharma Physio"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The presence of a blood\u2013brain barrier (BBB) prevents the delivery of most drugs to the brain. This characteristic limitation poses a major challenge to effective pharmacological treatment for numerous neurodegenerative diseases, particularly Alzheimer's disease. Delivering small interfering RNA (siRNA) via nanoparticles represents a highly promising approach for treating Alzheimer's disease. Nevertheless, developing a safe and efficient siRNA delivery system remains challenging. To enhance brain targeting and therapeutic efficacy, we developed an siRNA nanocarrier system based on PAH\u2010AM\u2010PEG\u2010ApoE (PAPA) nanoparticles (PAPA\/siRNA NPs), which facilitates BBB penetration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, an siRNA nanocarrier delivery system modified with ApoE peptide (PAPA\/siRNA NPs) developed by our research team was employed to simultaneously encapsulate BACE1\u2010siRNA and GSK3\u03b2\u2010siRNA. The PAPA\/siRNA NPs were prepared through self\u2010assembly and electrostatic binding. The particle size distribution profile and zeta potential of the PAPA\/siRNA NPs were analysed with dynamic light scattering, while its morphology was examined with transmission electron microscopy. For in\u00a0vitro assessments, flow cytometry, confocal laser scanning microscopy, PCR, and Western blotting were employed to evaluate the cellular uptake, gene silencing capacity, and endosomal escape. The biodistribution was investigated by in\u00a0vivo imaging technology, and the therapeutic effect on AD was verified in AD model mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The prepared PAPA\/siRNA NPs exhibited a regular spherical appearance with a uniform particle size distribution profile. In in\u00a0vitro cell experiments, the PAPA\/siRNA NPs demonstrated excellent cellular uptake ability and efficient endosomal escape. Meanwhile, the dual\u2010loaded siRNA nanocarrier delivery system effectively inhibited the expression of GSK3\u03b2 and BACE1 genes. In\u00a0vivo experimental results showed that the siRNA could successfully cross the BBB and deliver to the brain. It not only significantly prolonged the half\u2010life of siRNA but also greatly reduced the generation of pathological \u03b2\u2010amyloid and phosphorylated microtubule\u2010associated protein tau, showing excellent therapeutic effects in the treatment of AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In this study, we successfully constructed a brain\u2010targeted siRNA nanocarrier delivery system for double\u2010gene knockdown. This system can efficiently overcome the obstacle of the BBB, markedly alleviating cognitive and memory deficits in AD mice. It paves the way for novel strategies in the clinical treatment of AD and is expected to bring new breakthroughs and changes to the conquest of this disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/1440-1681.70108","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T10:48:09Z","timestamp":1772966889000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Blood\u2013Brain Barrier\u2010Permeable\n                    <scp>siRNA<\/scp>\n                    Nanodrugs With Dual\u2010Gene Knockdown for Alzheimer's Disease Therapy"],"prefix":"10.1111","volume":"53","author":[{"given":"Feng","family":"Su","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics China Pharmaceutical University  Nanjing China"},{"name":"Hefei Industrial Pharmaceutical Institute Co., Ltd, Anhui Provincial Key Laboratory of Drug Innovation and Advanced Pharmaceuticals  Hefei 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