Engineering the blood: Lipid nanoparticle platforms for ex vivo immune and hematopoietic cell therapies

Ex vivo gene delivery is a fundamental technology driving cellular therapeutics, required for CAR-T cells, engineered NK cells, reprogrammed macrophages, and genetically corrected HSPCs. Beyond nucleated immune effectors, this frontier is rapidly expanding to anucleate lineages like red blood cells and platelets. Traditionally, viral vectors have been widely utilized; however, their clinical translation is hindered by insertional mutagenesis, payload constraints, and complex manufacturing. As an alternative, electroporation has become the clinical standard for non-viral delivery, yet it intrinsically induces severe cytotoxicity and triggers a p53-dependent DNA damage response in HSPCs that compromises stem cell fitness. To address these critical bottlenecks, this review highlights LNP as a platform to overcome the limitations of conventional delivery methods. By facilitating physiological endocytosis and ultra-transient expression of nucleic acid payloads, LNP platforms abrogate p53 pathway activation and minimize cellular stress. Rationally designed LNPs achieve high delivery efficiencies across diverse blood lineages while preserving cell viability, innate functionality, and long-term in vivo repopulating capacity. By comprehensively discussing recent advancements in LNP formulation and next-generation RNA payload engineering, this review aims to provide actionable guidance to bench-side cell engineering to broad clinical applications.