Antibody-conjugated lipid nanoparticles for in vivo CAR-T cell engineering: From concept to clinical translation

Chimeric antigen receptor T cell therapy represents a transformative advancement in immunotherapy, wherein engineered T cells target tumor antigens, achieving high response rates in hematological malignancies. Its therapeutic applications have further expanded to infectious diseases, autoimmune diseases, and fibrosis. However, Chimeric antigen receptor T cell therapy still faces major unresolved limitations: poor infiltration into solid tumors, off-target toxicity, suppression in B cell malignancies, drug resistance, immunosuppressive tumor microenvironment, high manufacturing costs of cell therapies, and insufficient long-term persistence. Lipid nanoparticles have emerged as a revolutionary tool for mRNA vaccines and gene therapy. As a non-viral delivery system, lipid nanoparticles enable precise nucleic acid delivery via their unique molecular design, efficient encapsulation capacity, targetability, biocompatibility, and scalable manufacturing. They have been successfully applied in mRNA vaccines, providing a versatile platform for gene therapy. In recent years, lipid nanoparticles have innovatively addressed current limitations of immune cell therapies and expanded their therapeutic scope in ex vivo / in vivo mRNA-based chimeric antigen receptor engineering of immune cells by enabling modular, transient, and tissue-specific chimeric antigen receptor expression. This review systematically explores the cutting-edge advances in in vivo chimeric antigen receptor T cell engineering, highlights the advantages of Lipid nanoparticles over lentiviral vectors in terms of manufacturing processes, cytotoxicity, and safety, and discusses the application prospects and future directions of in vivo chimeric antigen receptor T cell engineering for disease treatment.