title: Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways.
abstract: Facing the threat of highly variable virus infection, versatile vaccination systems are urgently needed. Intranasal mRNA vaccination provides a flexible and convenient approach. However, the nasal epithelium remains a major biological barrier to deliver antigens to nasal associated lymphoid tissue (NALT). To address this issue, a potent polymer-based intranasal mRNA vaccination system for HIV-1 treatment was synthesized using cationic cyclodextrin-polyethylenimine 2k conjugate (CP 2k) complexed with anionic mRNA encoding HIV gp120. The delivery vehicle containing CP 2k and mRNA overcame the epithelial barrier by reversibly opening the tight junctions, enhanced the paracellular delivery of mRNA and consequently minimized absorption of toxins in the nasal cavity. Together with the excellent intracellular delivery and prolonged nasal residence time, strong system and mucosal anti-HIV immune responses as well as cytokine productions were achieved with a balanced Th1/Th2/Th17 type. Our study provided the first proof of evidence that cationic polymers can be used as safe and potent intranasal mRNA vaccine carriers to overcome the nasal epithelial barrier. The safe and versatile polymeric delivery system represents a promising vaccination platform for infectious diseases.
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Mengnan
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: You
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China. Electronic address: xunsun22@gmail.com.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D000281:Administration, Intranasal; D000818:Animals; D000917:Antibody Formation; D002460:Cell Line; D003505:Cyclodextrins / Q000737:chemistry*; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D018928:Immunity, Mucosal; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000276:immunology / Q000378:metabolism*; D011094:Polyethyleneimine / Q000737:chemistry*; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D014611:Vaccination
chemical_list: D016915:AIDS Vaccines; D003505:Cyclodextrins; D004337:Drug Carriers; D012333:RNA, Messenger; D011094:Polyethyleneimine
keywords: CD-PEI; Intracellular delivery; Nasal epithelial barrier; Paracellular delivery; mRNA vaccination