Nanomaterials Drive In Vivo CAR Immune Cells Engineering

Abstract

ABSTRACT Chimeric antigen receptor (CAR) immune cell therapy has emerged as a cornerstone of modern cell‐based medicine, demonstrating potent clinical efficacy against a range of malignant tumors and autoimmune diseases. Nevertheless, conventional ex vivo CAR immune cell manufacturing is hindered by complexity, high costs, and significant inter‐individual variability, which have limited its broad clinical application. These bottlenecks have prompted a paradigm shift toward in vivo CAR engineering, wherein nanocarriers directly deliver genetic material to circulating or tissue‐resident immune cells, substantially simplifying the production process. This review first outlines the evolution of CAR immune cell therapy and key limitations of ex vivo approaches and then examines major delivery platforms for in vivo approaches. Comparative analyses are presented across delivery efficiency, cellular tropism, and expression kinetics, with particular emphasis on delineating the mechanistic distinctions and application boundaries between transient and durable expression strategies. We further dissect the critical challenges, including receptor‐mediated non‐specific immune activation, nanocarrier‐associated immunogenicity constraining repeated administration, and delivery barriers imposed by the solid tumor microenvironment. Finally, the intrinsic trade‐off between therapeutic durability and biosafety across distinct delivery platforms is discussed, along with the necessity that their clinical translation hinges on systematic optimization of delivery precision, immune compatibility, and expression controllability.