Challenges in Exploiting Human H Ferritin Nanoparticles for Drug Delivery: Navigating Physiological Constraints

ABSTRACT Over the past two decades, ferritin has emerged as a promising nanoparticle for drug delivery, catalyzing the development of numerous prototypes capable of encapsulating a wide array of therapeutic agents. These ferritin‐based nanoparticles exhibit selectivity for various molecular targets and are distinguished by their potential biocompatibility, unique symmetrical structure, and highly controlled size. The hollow interior of ferritin nanoparticles allows for efficient encapsulation of diverse therapeutic agents, enhancing their delivery and effectiveness. Despite these promising features, the anticipated clinical advancements have yet to be fully realized. As a physiological protein with a central role in both health and disease, ferritin can exert unexpected effects on physiology when employed as a drug delivery system. Many studies have not thoroughly evaluated the pharmacokinetic properties of the ferritin protein shell when administered in vivo, overlooking crucial aspects such as biodistribution, clearance, cellular trafficking, and immune response. Addressing these challenges is crucial for achieving the desired transition from bench to bedside. Biodistribution studies need to account for ferritin's natural accumulation in specific organs (liver, spleen, and kidneys), which may lead to off‐target effects. Moreover, the mechanisms of clearance and cellular trafficking must be elucidated to optimize the delivery and reduce potential toxicity of ferritin nanoparticles. Additionally, understanding the immune response elicited by exogenous ferritin is essential to mitigate adverse reactions and enhance therapeutic efficacy. A comprehensive understanding of these physiological constraints, along with innovative solutions, is essential to fully realize the therapeutic potential of ferritin nanoparticles paving the way for their successful clinical translation.