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

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.