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Unlike linear mRNA, circular RNA (circRNA) lacks free ends, conferring exceptional resistance to exonuclease degradation and enabling sustained protein expression for days to weeks. Beyond their use as engineered therapeutics, endogenous circRNAs exhibit cancer\u2010associated expression patterns and persistence in biofluids, supporting complementary roles in tumor biology and as candidate biomarkers for diagnosis and longitudinal disease monitoring. This review argues that circular topology should be viewed as an active pharmacologic variable, not merely a stability enhancement. We dissect recent advances in cap\u2010independent translation initiation, including IRES elements and m\n                    <jats:sup>6<\/jats:sup>\n                    A\u2010driven mechanisms, rolling\u2010circle translation for multi\u2010epitope vaccine design, and programmable stability circuits that integrate tumor\u2010microenvironment cues such as miRNA signatures. Delivery innovations are equally transformative: antibody\u2010guided lipid nanoparticles and engineered extracellular vesicles enable increasingly selective RNA delivery, while local depot formulations and organ\u2010selective systemic routes expand therapeutic reach. Safety considerations are re\u2010evaluated as double\u2010edged tools\u2014innate immunogenicity can serve as a self\u2010adjuvant for cancer vaccines, whereas back\u2010splice\u2010junction neoantigens offer both vaccine opportunities and tolerance risks. Recent advances in scarless circularization, topology\u2010sensitive purification, dsRNA depletion, and lyophilized formulations have begun to address key manufacturing bottlenecks, although clinical\u2010scale recovery and process scalability remain insufficiently characterized. Key applications include circRNA cancer vaccines, transient CAR\u2010T\/NK cell engineering, tumor\u2010suppressor replacement, and circRNA\u2010encoded bispecific T\u2010cell engagers. The field now requires real\u2010time pharmacokinetic tracking, reproducible and scalable manufacturing, validated liquid\u2010biopsy assays, and indication\u2010specific regulatory pathways to translate circRNA from bench to bedside.\n                  <\/jats:p>","DOI":"10.1002\/bit.70344","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T05:16:05Z","timestamp":1786598165000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Circular Logic: Engineering Next\u2010Generation Circular RNA Therapeutics for Precision Oncology"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5481-5617","authenticated-orcid":false,"given":"Amr Ali Mohamed Abdelgawwad","family":"El\u2010Sehrawy","sequence":"first","affiliation":[{"name":"Internal medicine, Diabetes, Endocrinology and Metabolism Mansoura University Mansoura 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Medical Technologies Alnoor University Mosul Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laxmidhar","family":"Maharana","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Siksha \u2018O\u2019 Anusandhan (Deemed to be University) Bhubaneswar Odisha India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Singhal","sequence":"additional","affiliation":[{"name":"Centre for Research Impact and Outcome Chitkara University Rajpura Punjab India"},{"name":"Sharda School of Bio\u2010Science &amp; Technology Sharda University Greater Noida India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeraj","family":"Bainsal","sequence":"additional","affiliation":[{"name":"University Institute of Pharma Sciences Chandigarh University Mohali Punjab 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