The Nanoparticle Delivery Gap in Immune Cell Engineering: From Uptake to Endosomal Escape

Abstract: Although therapeutic opportunities beyond the scope of either field alone are offered by the combination of immune cell treatment and nanotechnology, a dominant nanoparticle design for immune-cell engineering has not been yielded by two decades of research. Here, it is contended that this lack of advancement is the result of a misdirected focus: endosomal escape, rather than cellular uptake, is held to be the actual rate-limiting stage in cytosolic distribution, even though cellular uptake is the target of most optimization efforts. Adopting endosomal escape as a unifying framework, this review examines the mechanisms governing nanoparticle–immune cell interactions, adopting endosomal escape as a unifying framework, this review examines the mechanisms governing nanoparticle–immune cell interactions, from uptake routing and intracellular trafficking to immune activation, and derives cell-type-specific design principles, escape efficiency, and a decision framework for pairing escape mechanisms with target cell types. In addition, cell-type engineering is examined through the "delivery gap” that separates clinical success in solid tumors from failure in hematologic cancers. Rather than being classified neutrally, nanocarrier platforms are evaluated here according to translational viability. Manufacturing, regulatory, and safety considerations are synthesized into useful decision tools, and the review is concluded with a falsifiable ten-year plan and the main unanswered concerns in the field. Standardized endosomal escape and repeatable production are identified as the most manageable, high-impact short-term priorities by which nano-engineered immune cell treatments can be brought closer to the clinic. Keywords: nanoparticles, immune cell therapy, endosomal escape, CAR-T, lipid nanoparticles, non-viral delivery, clinical translation