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However, their clinical translation is significantly hindered by sequential biological barriers, necessitating highly efficient delivery systems. Biomedical polymers, owing to their tunable physicochemical properties, versatile structural engineering, and robust biocompatibility, have become a cornerstone in the development of nucleic acid nanocarriers. This review provides a comprehensive overview of polymeric delivery vehicles for nucleic acid vaccines, with a specific focus on rational design strategies tailored to overcome complex physiological barriers. We systematically dissect how functional polymer engineering\u2014including interfacial shielding, targeted ligand modification, membrane perturbation, and stimuli-responsive disassembly\u2014facilitates systemic circulation, antigen-presenting cell uptake, endosomal escape, and intracellular cargo release. Furthermore, we critically examine the persistent bottlenecks in current delivery platforms, such as the restricted uptake in primary immune cells and the fundamental inefficiencies of endosomal escape, while outlining future perspectives for the development of next-generation, clinically translatable polymeric nucleic acid vaccines.<\/jats:p>","DOI":"10.1021\/acsami.6c09208","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:12:13Z","timestamp":1784823133000},"page":"40122-40157","source":"Crossref","is-referenced-by-count":0,"title":["Polymeric Delivery Vehicles for Nucleic Acid Vaccines: Design Strategies and Biological Barriers"],"prefix":"10.1021","volume":"18","author":[{"given":"Pijun","family":"Su","sequence":"first","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilin","family":"Yuan","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuo","family":"Dong","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4364-2196","authenticated-orcid":true,"given":"Huapan","family":"Fang","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361005"]},{"name":"Shenzhen Research Institute of Xiamen University , ,","place":["Shenzhen, China, 518000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-3744","authenticated-orcid":true,"given":"Huayu","family":"Tian","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"2026080518111919700_cit1","doi-asserted-by":"publisher","first-page":"S28","DOI":"10.1016\/j.vaccine.2023.07.033","article-title":"Modeling the impact of vaccination for the immunization agenda 2030: Deaths averted due to vaccination against 14 pathogens in 194 countries from 2021 to 2030","volume":"42","author":"Carter","year":"2030","journal-title":"Vaccine"},{"issue":"7","key":"2026080518111919700_cit2","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.3390\/vaccines11071264","article-title":"The promising potential of reverse vaccinology-based next-generation vaccine development over conventional vaccines against antibiotic-resistant bacteria","volume":"11","author":"Khalid","year":"2023","journal-title":"Vaccines"},{"key":"2026080518111919700_cit3","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2022.105828","article-title":"Novel coronavirus mutations: Vaccine development and challenges","volume":"173","author":"Luo","year":"2022","journal-title":"Microb. 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