Designing Protein-Based Nanoparticles for Therapeutic Applications.

Protein-based nanoparticles (PNPs) represent a versatile and promising class of nanocarriers for biomedical applications, offering inherent biocompatibility, biodegradability, and functional adaptability. By leveraging the diverse structural and chemical characteristics of natural and engineered proteins, certain PNP systems have demonstrated the potential to achieve precise control over drug loading, release kinetics, and targeting under specific design strategies, making them attractive platforms for therapeutic and diagnostic delivery. In this review, we aim to provide a comprehensive understanding of the design of protein-based nanoparticles and their clinical translation by conducting an in-depth analysis of recent studies on protein nanoparticles, in conjunction with protein-related formulations approved by the FDA in the past five years. We outline the biological rationale for their use and examine key challenges─including stability, immunogenicity, and manufacturing scalability─that impact their clinical translation. Design strategies such as surface modification, ligand targeting, modularity, stimuli-responsive engineering, and computational approaches are highlighted for their role in overcoming these barriers and enhancing performance. We further explore applications across neurological disorders, cancer, infectious diseases, and diagnostics, illustrating the broad potential of these systems. Finally, we provide an in-depth analysis of the clinical landscape and manufacturing challenges of protein-based therapeutics, highlighting the potential of emerging in vivo gene and protein editing technologies to accelerate the development of innovative protein drugs with the aim of facilitating the clinical translation of PNPs. By synthesizing insights from materials science, biology, and medicine, this Perspective aims to guide the rational design of next-generation PNPs for effective and personalized healthcare solutions.