Challenges in Nanoparticle Delivery for Immune Cell Engineering: From Cell Uptake to Escaping Internal Compartments

Standardized endosomal escape and repeatable production are identified as high-impact short-term priorities for advancing nano-engineered immune cell treatments.

• The combination of immune cell treatment and nanotechnology has not produced a dominant nanoparticle design after two decades of research.
• Endosomal escape may be the actual rate-limiting stage in delivering nanoparticles to the cell's interior, contrary to the focus on cellular uptake.
• Mechanisms of nanoparticle-immune cell interactions, including uptake routing and intracellular trafficking, are essential for understanding how to enhance immune activation.
• Cell-type-specific design principles and escape efficiency are necessary to optimize nanoparticle applications for different immune cells.
• The review evaluates nanocarrier platforms based on their translational viability, incorporating manufacturing and regulatory considerations.
• A ten-year plan with unresolved questions in the field is proposed, aiming to bridge the gap between clinical success in solid tumors and failures in hematologic cancers.

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