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Here, we present a spatiotemporally organized 3D BBB model engineered via dynamic microenvironmental regulation. Temporally controlled enzymatic modulation of an alginate\/collagen dual-network hydrogel enabled transition in matrix properties from strong to weak mechanical confinement, thereby triggering the embedded cells to shift from a quiescent to an active state and further enabling the construction of a BBB model with sequential endothelial and supporting cell development. The resulting 3D BBB model exhibits improved barrier integrity, reduced macromolecular leakage, and physiologically relevant drug-selective permeability. This strategy demonstrates that temporally controlled microenvironmental cues can guide multicellular tissue development, providing a versatile platform for neurovascular research and central-nervous-system-targeted drug evaluation.<\/jats:p>","DOI":"10.34133\/research.1408","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T05:11:38Z","timestamp":1785820298000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["Microenvironment-Driven 3-Dimensional Biofabrication Enables Sequential Maturation of the Blood\u2013Brain Barrier"],"prefix":"10.34133","volume":"9","author":[{"given":"Sen","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory for Manufacturing System Engineering, School of Mechanical Engineering, \rXi\u2019an Jiaotong University, Xi\u2019an, China."},{"name":"National Innovation Platform (Center) for Industry-Education Integration of Medical 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