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Despite decades of empirical process optimization, intrinsic genomic instability, including segmental aneuploidy and dynamic chromatin rearrangements, continues to limit the durability of engineered phenotypes under sustained viral burden and bioreactor stress. Here, we review the expanding engineering toolkit for the Vero lineage across a three\u2010layered functional framework: the membrane interface, cytoplasmic foundry, and nuclear blueprint, evaluating translational prospects at each level. Receptor transplantation and morphological reprogramming have broadened viral entry range and enabled suspension\u2010adapted culture formats, while metabolic flux management and temporally controlled apoptosis modulation have addressed intracellular production bottlenecks, albeit often with trade\u2010offs between productivity, biosafety, and long\u2010term population stability. At the genomic level, targeted perturbations of transcriptional regulators and emerging epigenetic interventions offer more durable gains, yet expression drift, clonal heterogeneity, and karyotypic instability during extended passaging highlight the need for locus\u2010level precision rather than constitutive trait installation. Looking forward, infection\u2010responsive dynamic logic circuits and the systematic identification of Vero\u2010specific genomic safe harbors could shift the paradigm toward a conditionally responsive manufacturing architecture. Collectively, these advances suggest a pathway for transitioning the Vero lineage from a passive, empirically optimized biological substrate into a conditionally responsive, genomically stable, and programmable platform for modern vaccine preparedness.<\/jats:p>","DOI":"10.1002\/bit.70374","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:20:31Z","timestamp":1789021231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineering the Vero Cell Lineage: Toward a Programmable Vaccine Manufacturing Platform"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8045-0683","authenticated-orcid":false,"given":"Hanfu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medical Genetics Institute of Medical Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College Kunming Yunnan 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