Amphiphilic Zwitterionic Polymers Induce Liposome Morphogenesis into Nanodiscs for Deep Glioblastoma Infiltration

ABSTRACT Glioblastoma therapy is severely constrained by the blood–brain barrier (BBB) and limited intratumoral penetration. Here, we report a de novo synthesized amphiphilic zwitterionic copolymer that co‐assembles with phospholipids into protein‐free nanodiscs (zNDs, ∼15.5 nm). Liposome co‐flotation and Förster resonance energy transfer (FRET) assays reveal a three‐stage morphogenetic process: polymer insertion, membrane disruption, and liposome‐to‐nanodisc reassembly through membrane remodeling. The resulting zNDs exhibit high colloidal stability under physiological conditions and efficiently cross the BBB via choline transporter‐mediated transcytosis. In orthotopic glioblastoma models, zNDs penetrate tumors deeply, enter cells through clathrin‐mediated endocytosis, and escape endo‐lysosomal compartments. Incorporation of lipid–drug conjugates allows delivery of honokiol, which disassembles 3D tumor spheroids, suppresses tumor growth in orthotopic models, and extends median survival by nearly 2.5‐fold without systemic toxicity. This study establishes a modular, protein‐free nanodisc platform that integrates rational polymer design with active BBB transport, offering a versatile strategy for deep therapeutic delivery in central nervous system malignancies and providing mechanistic principles that guide future optimization of BBB‐penetrant nanocarriers.