Stability-Enhanced Therapeutic Artificial Cells Based on a Lipid-Polymer Integrated Architecture

Current artificial cells often lack robustness in the face of the complex physiological milieu. Additionally, the strategies for mimicking natural cargo exchange mostly rely on biological techniques, which involve integrating native channel proteins or adopting intact natural cell membranes. Herein, we propose a rational chemical design strategy to construct artificial mini cells (MCs) based on a lipid-polymer integrated architecture. Our MCs show three key merits, including robust structural stability, controllable metabolic reactions, and convenient surface functionalization for diverse biomedical applications. MCs adopt a lipid-polymer integrated architecture, where a cross-linked zwitterionic polymer in situ grown on the phospholipid membrane acts as the conceptually synthesized cytoskeleton mimic, ensuring structural stability and easy functionalization. Azobenzene-gated lipids are incorporated to act as light-responsive channel protein mimics, enabling spatiotemporal regulation of membrane permeability and metabolic reactions. As a proof of concept, therapeutic artificial MCs with tumor tropism, surface-immobilized aPDL1 proteins, and internally encapsulated glucose oxidase-catalase (GOx-Cat) multi-enzyme system were rationally designed, named aPDL1-Tt-MC(GOx + Cat). aPDL1-Tt-MC(GOx + Cat)s possess zwitterionic ionizable pyridine carboxybetaine moieties for tumor tropism, the GOx-Cat system for light-controlled glucose-to-O₂ conversion to drive deep tumor infiltration, and surface-immobilized aPDL1 to block PD-1/PD-L1 recognition for enhanced antitumor efficacy.