Overcoming the On‐Target Toxicity in Antibody‐Mediated Therapies via an Indirect Active Targeting Strategy

Abstract Antibody‐based therapies could be led astray when target receptors are expressed on nontarget sites, and the on‐target toxicity poses critical challenges to clinical applications. Here, a biomimetic indirect active targeting (INTACT) strategy is proposed based on receptor expression disparities between nontarget sites and the targets. By prebinding the antibodies using cell membrane vesicles with appropriate receptor expressions, the INTACT strategy could filter out the interactions on nontarget sites due to their inferior receptor expression, whereas ensure on‐demand release at the targets by competitive binding. The strategy is verified on CD47 antibody, realizing drastic alleviation of its clinically concerned hematotoxicity on a series of animal models including humanized patient‐derived xenograft platforms, accompanied by preferable therapeutic effects. Furthermore, the INTACT strategy proves extensive applicability for various systems including antibody, antibody–drug conjugate, and targeted delivery systems, providing a potential platform refining the specificity for frontier antibody‐related therapies.