Where do we stand now regarding protein nanoparticles? Perspectives from the Six Thinking Hats framework

INTRODUCTION: This review highlights the critical role of protein nanoparticles (PNPs) in advancing precision therapy and introduces Edward de Bono's Six Thinking Hats (STH) framework as an innovative, structured paradigm to systematically analyze their development beyond traditional review models. AREAS COVERED: This study conducted a systematic search of the PubMed and Web of Science databases (2016-2025) using the keywords 'protein nanoparticles,' 'drug delivery,' and 'Six Thinking Hats.' Peer-reviewed literature addressing the design, clinical translation, and overcoming of bottlenecks in PNPs was rigorously screened to ensure the rigor of this review. Using the STH framework, we modularly analyze PNPs' core characteristics, clinical advantages (e.g. biocompatibility, targeting), key challenges (immunogenicity, production scalability), and innovative solutions (surface engineering, biomimetic camouflage). A phased translational roadmap is outlined. EXPERT OPINION: The STH framework provides a multidimensional review methodology that effectively identifies and addresses the core 'stability-production-targeting' bottleneck. It holds significant promise for driving the clinical translation of PNPs and can be scaled to other nanodelivery systems to foster interdisciplinary innovation.