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Here, we reveal that hepatitis B virus (HBV) pregenomic RNA (pgRNA) exploits liquid-liquid phase separation (LLPS) inside the capsid to sculpt its architecture. Multiscale molecular dynamics (MD) simulations, supplemented by biochemical assays, show that pgRNA coalesces into a hollow, shell-like condensate along the inner capsid surface, with coexisting low- and high-density regions. Electrostatic interactions between pgRNA and the disordered C-terminal domain of capsid protein primarily govern condensate formation. LLPS drives the establishment of microphases composed of nematically aligned RNA hairpin arrays interspersed by domains rich in flexible single-stranded RNA linkers, achieving an optimal balance between structural order and dynamic flexibility. Intriguingly, although the ensemble-averaged pgRNA density exhibits icosahedral symmetry, individual simulation snapshots display pronounced heterogeneity, indicating symmetry breaking at the single-particle level. In addition, LLPS-induced hollow-shell architecture of pgRNA genome promotes long-range RNA base-pairing and enhances polymerase mobility, which may facilitate the functional dynamics of polymerase during reverse transcription. Our findings uncover a capsid-confined LLPS mechanism that orchestrates viral genome structure and dynamics, offering new targets for antiviral intervention.<\/jats:p>","DOI":"10.1038\/s41467-026-69689-2","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T17:09:04Z","timestamp":1771520944000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Structural organization of HBV pgRNA genome driven by phase separation in capsid confinement"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7316-8301","authenticated-orcid":false,"given":"Yunqiang","family":"Bian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6660-9052","authenticated-orcid":false,"given":"Hai","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1493-7868","authenticated-orcid":false,"given":"Yi","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2679-4075","authenticated-orcid":false,"given":"Wenfei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5441-0302","authenticated-orcid":false,"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"69689_CR1","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/s42254-020-00267-1","volume":"3","author":"RF Bruinsma","year":"2021","unstructured":"Bruinsma, R. 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