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Lipid nanoparticles have enabled early clinical successes, but they can be limited by liver-dominant biodistribution, long-term storage stability, and systemic tolerability. Polymeric delivery systems offer a versatile alternative, with tunable physicochemical properties enabling precise control over mRNA complexation, protection, release, and targeting. This review examines recent progress across polyethyleneimine derivatives, poly(\u03b2-amino ester)s, poly(amino acid)s, polyesters, dendrimers, charge-altering releasable transporters, and lipid-polymer hybrids. We highlight strategies such as structural modification, stimuli-responsive designs, and high-throughput polymer screening that enhance stability, reduce cytotoxicity, and enable organ- or cell-specific delivery. Addressing challenges in immunogenicity, biodistribution, and manufacturing scalability will be pivotal to translating these innovations into safe and effective mRNA therapeutics.<\/jats:p>","DOI":"10.3390\/genes17060646","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:58:38Z","timestamp":1780473518000},"page":"646","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Polymeric Delivery System for mRNA Therapeutics: Design Principles and Recent Advances"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0217-5184","authenticated-orcid":false,"given":"Sidi","family":"Bao","sequence":"first","affiliation":[{"name":"Charles Institute of Dermatology, School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2189-0046","authenticated-orcid":false,"given":"Irene Rose","family":"Reuben","sequence":"additional","affiliation":[{"name":"Charles Institute of Dermatology, School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3680-3043","authenticated-orcid":false,"given":"Josie","family":"Ward","sequence":"additional","affiliation":[{"name":"Charles Institute of Dermatology, School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5053-0611","authenticated-orcid":false,"given":"Wenxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Charles Institute of Dermatology, School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8702-3859","authenticated-orcid":false,"given":"Xianqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Charles Institute of Dermatology, School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1016\/j.matt.2022.03.006","article-title":"The Roles of Polymers in mRNA Delivery","volume":"5","author":"Huang","year":"2022","journal-title":"Matter"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1039\/D4PY00206G","article-title":"Rational Design of Polymer-Based mRNA Delivery Systems for Cancer Treatment","volume":"15","author":"Wan","year":"2024","journal-title":"Polym. 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