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Here, we provide direct experimental visualization showing that crowding\u2010induced condensation of membrane\u2010anchored macromolecules above the bilayer interface reorganizes membrane dynamics and gives rise to spatially heterogeneous lipid mobility. Both PEGylated lipids and membrane\u2010anchored proteins undergo surface\u2010density\u2010driven condensation on supported lipid bilayers (SLBs), forming immobile regions that constrain lipid diffusion. Notably, the condensation threshold varies inversely with poly(ethylene glycol) chain length and surface density, defining a quantitative relationship between molecular size and crowding strength. To directly visualize these crowding\u2010induced structures, we employed a nanodisc\u2010mediated lipid delivery (\u201cnanodelivery\u201d) approach, revealing a clear correspondence between condensed crowder regions and diffusion barriers reminiscent of the picket\u2010fence model of live\u2010cell membranes. Similar behavior in protein\u2010crowded SLBs demonstrates the generality of this crowding\u2010driven mechanism. Using minimal two\u2010layer and three\u2010layer reconstituted architectures, we further demonstrate that surface density and macromolecular crowding above the membrane function as tunable control parameters that drive phase transitions within membrane\u2010tethered macromolecular layers, independent of anchoring chemistry, while the underlying lipid bilayer remains laterally continuous. Extension of this framework to living cells reveals analogous suppression of membrane mobility under high surface\u2010density conditions, indicating that this crowding\u2010induced reorganization is not restricted to SLBs model systems. Together, these findings establish surface\u2010density\u2010driven phase transitions of membrane\u2010anchored macromolecules as a general physical mechanism underlying lateral membrane inhomogeneity and position nanodelivery as a versatile approach for interrogating membrane organization across synthetic and biological systems.<\/jats:p>","DOI":"10.1002\/pro.70822","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:17:07Z","timestamp":1791994627000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Crowding\u2010driven condensation and membrane reorganization"],"prefix":"10.1002","volume":"35","author":[{"given":"Ru\u2010Hsuan","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Chemistry National Tsing Hua University  Hsinchu 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