{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T08:51:55Z","timestamp":1764319915518,"version":"3.46.0"},"reference-count":42,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shandong Weigao Litong Biological Products Co., Ltd."},{"name":"Weirui Biotechnology (Kunming) Co., Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background: Rabies virus (RABV) causes approximately 59,000 human deaths annually. Current pre- and post-exposure vaccination relies on inactivated vaccines (INVs) with limited yield and immunogenicity. We engineered a dual-cationic LNP-based nucleocapsid-like nanostructure (NLS) that co-encapsulates RABV G-mRNA and recombinant RABV-N to engage MHC-I\/II pathways and enhance protection. Methods: A pVAX-RABV-G plasmid containing 5\u2032\/3\u2032UTRs, Kozak, and poly(A) was transcribed in vitro. RABV-N with an N-terminal 6\u00d7 His tag was expressed in E. coli BL21(DE3) and purified by Ni-Sepharose affinity chromatography. Dual-cationic LNPs (DHA, DOTAP Cl, mPEG-DTA2K, DOPC) were formulated by microfluidics at a 4:1 (G-mRNA:RABV-N) mass ratio. Vaccine quality was assessed by encapsulation efficiency, DLS, PDI, zeta potential, and TEM. Mice received empty LNPs, INV, G-mRNA, or NLS under varied schedules and doses. ELISA measured RABV-G\/N-IgG; RFFIT determined neutralizing antibody (nAb) titers; ELISPOT quantified CTL response; qPCR assessed T-cell activation genes. On day 35 after the first immunization of vaccines, mice were challenged intramuscularly with 25 LD50 of CVS-24. Results: G-mRNA purity was &gt;95% and drove strong RABV-G expression in 293T cells. Purified RABV-N was approximately 52 kDa, &gt;90% pure, and reactive to anti-His and anti-N antibodies. NLS achieved &gt;95% encapsulation, a diameter of 136.9 nm, PDI 0.09, and a +18.7 mV zeta potential. A single dose yielded approximately 10 IU mL\u22121 nAb by day 7; two doses peaked at approximately 1000 IU mL\u22121. Mice showed 100% survival and no viral rebound in brain, spinal cord, and sciatic nerve. NLS induced stronger MHC-I\/II-linked cellular immunity and higher RABV G\/N-specific IFN-\u03b3 spot frequencies than G-mRNA or INV. Conclusions: The dual-antigen NLS vaccine co-delivering G-mRNA and RABV-N via dual-cationic LNPs robustly activates MHC-I\/II, rapidly generates high-titer nAb (\u226510 IU mL\u22121 within 1 week), and sustains potent CD8+ CTL and CD4+ Th responses. A two-dose regimen (days 0 and 21) conferred complete protection, supporting the NLS platform as a next-generation rabies vaccine candidate.<\/jats:p>","DOI":"10.3390\/vaccines13121196","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T15:56:41Z","timestamp":1764172601000},"page":"1196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Rabies Virus Nucleocapsid-like Nanostructure Vaccine Based on Dual-Cationic Lipid Nanoparticles"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2307-880X","authenticated-orcid":false,"given":"Zhixiao","family":"Zhang","sequence":"first","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation Center, Kunming 650000, China"},{"name":"Shandong Weigao Litong Biological Products Co., Ltd., Weihai 264200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation Center, Kunming 650000, China"},{"name":"Shandong Weigao Litong Biological Products Co., Ltd., Weihai 264200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changyong","family":"Mu","sequence":"additional","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation Center, Kunming 650000, China"},{"name":"Shandong Weigao Litong Biological Products Co., Ltd., Weihai 264200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5242-3000","authenticated-orcid":false,"given":"Kaili","family":"Ma","sequence":"additional","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation Center, Kunming 650000, China"},{"name":"Shandong Weigao Litong Biological Products Co., Ltd., Weihai 264200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongxiu","family":"Gao","sequence":"additional","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation Center, Kunming 650000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang\u2019e","family":"Liu","sequence":"additional","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation Center, Kunming 650000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Feng","sequence":"additional","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation Center, Kunming 650000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowu","family":"Peng","sequence":"additional","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation Center, Kunming 650000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiuqi","family":"Li","sequence":"additional","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation Center, Kunming 650000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahui","family":"Li","sequence":"additional","affiliation":[{"name":"Weirui Biotechnology (Kunming) Co., Ltd., Ciba Biotechnology Innovation Center, Kunming 650000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuiyan","family":"Zou","sequence":"additional","affiliation":[{"name":"Shandong Weigao Litong Biological Products Co., Ltd., Weihai 264200, 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17091","DOI":"10.1038\/nrdp.2017.91","article-title":"Rabies","volume":"3","author":"Fooks","year":"2017","journal-title":"Nat. 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