Benchmarking Protein Nanoparticles for Drug Delivery and Clinical Translation

ABSTRACT Protein nanoparticles (PNs) are emerging as versatile, biocompatible platforms for drug delivery, leveraging their intrinsic biodegradability, molecular specificity, and structural tunability. They improve drug stability, prolong circulation, and enable targeted delivery, making them promising in cancer nanomedicine. This review classifies PNs into native‐ordered, native‐amorphous, and denatured categories, each distinguished by unique assembly strategies and pharmacokinetic behaviors. We discuss fabrication methods like emulsification, crosslinking, and desolvation. We also examine functionalization strategies—including PEGylation, Fc fusion, and lipidation—that enhance tumor selectivity and therapeutic efficacy. A systematic evaluation framework, encompassing physicochemical characterization, in vitro assays, and in vivo assessments, is essential for their successful translation. While clinical use is currently limited, examples like nab‐paclitaxel and virus‐like particle (VLP)‐based vaccines demonstrate their potential. We highlight persistent challenges, such as a lack of standardized evaluation methods and regulatory guidelines, and identify opportunities for innovation to accelerate the development of next‐generation protein nanomedicines.