Tumor Microenvironment‐Tailored Weakly Cell‐Interacted Extracellular Delivery Platform Enables Precise Antibody Release and Function

Abstract Precise delivery of extracellularly functional protein drugs is limited by the drawback in that the protective carrier often causes undesirable cellular uptake of these therapeutic agents. Here, the design of a weakly cell‐interacted, nanosized, environment‐responsive vehicle (WINNER) with rational phosphorylcholine (PC) surface filling ratios capable of precise extracellular delivery of therapeutic agents for enhanced tumor suppression is reported. Highly hydrophilic zwitterionic PC and enzyme‐responsive peptides are engineered into the functional shell of WINNER which reasonably covers the inner protein. It is demonstrated that rationally controlled PC surface filling ratios (50.5–58.3%) are necessary for weakening interactions between the cell and WINNER whilst providing enough sites on WINNER for enzyme recognition. Consequently, WINNER (50.5–58.3%) can protect inner cargos from cellular uptake and undergo enzymatic degradation, resulting in precise extracellular release of inner protein, such as therapeutic monoclonal antibody (mAb). After intravenous administration, therapeutic mAb nimotuzumab‐loaded WINNER (51.2%) shows highest in vivo antitumor activity compared with free nimotuzumab or nimotuzumab‐loaded PC‐free nanocarrier in a lung adenocarcinoma xenograft tumor animal model. This work presents a simple and flexible approach to design precise extracellular delivery platform which can uncage the therapeutic power of extracellular targeting therapeutic agents.