{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T13:22:36Z","timestamp":1787404956403,"version":"build-2736575974"},"reference-count":231,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008136","name":"Case Western Reserve University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008136","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA248019"],"award-info":[{"award-number":["R01CA248019"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA266256"],"award-info":[{"award-number":["R01CA266256"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>mRNA therapeutics are transitioning from transient anti-viral vaccines into precise cancer immunotherapies capable of orchestrating potent antigen-specific T-cell and humoral responses. However, therapeutic resistance within immunologically \u201ccold\u201d tumors remains a formidable barrier, necessitating multiaxial optimization across transcript architecture, neoantigen selection, delivery vector engineering, and tumor microenvironment (TME) reprogramming. This review synthesizes critical breakthroughs in mRNA biochemistry\u2014including chemical nucleotide modifications, optimized untranslated regions, structural codon adjustments, and stringent purification methodologies\u2014that extend transcript longevity while limiting off-target reactogenicity to maximize functional antigen expression. We evaluate multiomic neoantigen discovery workflows leveraging genomics, transcriptomics, immunoproteomics, and computational HLA-binding algorithms to refine patient-specific target selection. Next, we dissect advanced lipid nanoparticles, surface-functionalized biomaterials, and engineered extracellular vesicles optimized to enhance antigen-presenting cell tropism and lymphoid homing. We further detail how vaccine-induced cytokine fluxes actively remodel the TME, successfully reversing local immune tolerance and driving robust effector leukocyte infiltration into the tumor stroma. Specifically, we highlight the convergence of mRNA-mediated cytokine signaling and epigenetic imprinting, which cooperatively induce trained immunity for durable preventive surveillance. Finally, we delineate rational combinations with immune checkpoint blockades while addressing translational challenges: identifying predictive biomarkers, mapping presentation kinetics, and structuring adaptive clinical trial frameworks.<\/jats:p>","DOI":"10.1093\/pcmedi\/pbag019","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:20:38Z","timestamp":1783430438000},"source":"Crossref","is-referenced-by-count":0,"title":["Beyond the genetic code: orchestrating epigenetic and immune landscapes with multivalent mRNA-exosome vaccines"],"prefix":"10.1093","volume":"9","author":[{"given":"Huiqin","family":"Bian","sequence":"first","affiliation":[{"name":"Department of Medicine, The MetroHealth System, Case Western Reserve University , Cleveland, OH 44109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Tse","sequence":"additional","affiliation":[{"name":"Department of Medicine, The MetroHealth System, Case Western Reserve University , Cleveland, OH 44109 ,","place":["USA"]},{"name":"Cell and Gene Therapy Institute, The MetroHealth System, Case Western Reserve University , Cleveland, OH 44109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5457-5358","authenticated-orcid":false,"given":"Gang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cell Systems & Anatomy Department of Pathology & Laboratory Medicine UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine Mays Cancer Center at UT Health San Antonio , San Antonio, TX 78229 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5347-8345","authenticated-orcid":false,"given":"Shujun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine, The MetroHealth System, Case Western Reserve University , Cleveland, OH 44109 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