Facile-prepared FGF21/zinc nanocomplex for efficient brain delivery in ischemic stroke treatment
image: Via non-covalent interactions, the self-assembly of FGF21, zinc, and PVP constructed FGF21/Zinc NC, which promoted the FGF21 accumulation in the brain, protected neuronal cells from oxidative stress, and suppressed the overactivation of microglia and astrocytes to maintain brain environment homeostasis.
Credit: Nano Research, Tsinghua University Press
Protein-based therapeutics represent one of the most promising frontiers in modern medicine, offering targeted treatment options for a wide range of diseases from neurological disorders to metabolic conditions. However, their clinical application has been persistently hampered by two fundamental pharmacological challenges. First, therapeutic proteins such as the neuroprotective fibroblast growth factor 21 (FGF21) exhibit disappointingly short in vivo half-lives, typically ranging from just 1~3 hours in circulation. Second, conventional protein modification strategies, particularly polyethylene glycol (PEG) conjugation (PEGylation), while effective in prolonging circulation time, often lead to unpredictable alterations in protein conformation and consequent loss of biological activity. This "stability-activity" paradox has remained a critical bottleneck in protein drug development for decades.
Professor Lin Li's research team at Wenzhou Medical University has published groundbreaking research in Nano Research, demonstrating an innovative zinc-coordinated protein delivery technology that utilizes non-covalent interactions, successfully overcoming long-standing challenges in therapeutic protein formulation. “By employing Autodock Vina molecular docking, the interaction mechanisms between FGF21 and zinc were simulated. We innovatively selected zinc ions as coordination centers and rationally designed a polyvinylpyrrolidone (PVP)-stabilized FGF21/zinc nanocomplex delivery system based on structural insights,” said Xiaoyan Bao, Ph.D., senior corresponding author of the study, lecturer in the School of Pharmaceutical Sciences at Wenzhou Medical University.
The pharmacological advantages of this novel delivery platform are truly transformative. In the photothrombosis-induced ischemic stroke mouse model, the FGF21/Zinc NC demonstrated outstanding therapeutic efficacy. Compared to free FGF21, the nanocomplex showed significantly improved pharmacokinetic properties, exhibiting a 3-fold extension in plasma half-life and over 3-fold greater drug accumulation in brain tissue. Both in vitro and in vivo studies consistently demonstrated the superior performance of FGF21/Zinc NC across multiple therapeutic dimensions: it effectively scavenged reactive oxygen species (ROS) in neurons, and simultaneously suppressed neuroinflammatory responses by modulating the abnormal activation of both microglia and astrocytes. Particularly noteworthy was the nanocomplex's ability to reduce cerebral infarct volume by 45% and significantly accelerate the recovery of motor functions in stroke model mice.
This work not only provides an elegant solution to the protein stability-activity trade-off but also establishes a new framework for metal-ion coordinated protein delivery that could inspire next-generation biologics development across the pharmaceutical industry.
About Nano Research
Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.