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Yet mRNA delivery remains centered on intramuscular vaccination and intravenous administration, largely optimized for systemic adaptive immunity or circulation\u2010mediated biodistribution. Many localized diseases, however, are confined to tissues or compartments accessible by topical, transdermal, inhaled, oral, catheter\u2010based, ocular, or intra\u2010articular administration without initial reliance on circulation. For these diseases, the therapeutic objective is likewise local: therapeutically relevant mRNA expression occurs within the affected tissue, and efficacy derives predominantly from the local biological activity of the encoded protein rather than from downstream systemic effects initiated by local expression. This therapeutic paradigm is defined here as Anatomically Accessible Local mRNA Therapeutics (ALmT). The review first distinguishes ALmT from intravenous mRNA delivery and intramuscular mRNA vaccination, then organizes site\u2010specific barriers and engineering strategies across major anatomical sites. It further examines disease\u2010focused ALmT applications, highlighting protein restoration, cytokine or growth\u2010factor supplementation, local antibody\u2010fragment production, regenerative modulation, and tissue repair. Finally, it discusses general design principles, quantitative PK\/PD evaluation, repeat\u2010dose safety, and clinical translation. Overall, the ALmT framework may facilitate the design, quantitative evaluation, and clinical translation of mRNA therapies for localized diseases.<\/jats:p>","DOI":"10.1002\/adma.75381","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:23:08Z","timestamp":1791976988000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anatomically Accessible Local mRNA Therapeutics: From Anatomical Access to Disease\u2010Focused Applications"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9234-1530","authenticated-orcid":false,"given":"Yashi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Basic Medicine State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Hubei Key Laboratory For Drug Target Research and Pharmacodynamic Evaluation Huazhong University of Science and Technology  Wuhan China"},{"name":"Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5309-5778","authenticated-orcid":false,"given":"Ruoyi","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Basic Medicine State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Hubei Key Laboratory For Drug Target Research and Pharmacodynamic Evaluation Huazhong University of Science and Technology  Wuhan 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