Challenges and progress of neurodrug: bioactivities, production and delivery strategies of nerve growth factor protein

Nerve growth factor (NGF) is a vital cytokine that plays a crucial role in the development and regeneration of the nervous system. It has been extensively studied for its potential therapeutic applications in various neural diseases. However, as a protein drug, limited natural source seriously hinders its translation and clinical applications. Conventional extraction of NGF from mouse submandibular glands has a very high cost and potentially induces immunogenicity; total synthesis and semi-synthesis methods are alternatives, but have difficulty in obtaining correct protein structure; gene engineering of plant cells is thought to be non-immunogenic, bioactive and economical. Meanwhile, large molecular weight, high polarity, and negative electrical charge make it difficult for NGF to cross the blood brain barrier to reach therapeutic targets. Current delivery strategies mainly depend on the adenovirus and cell biodelivery, but the safety and efficacy remain to be improved. New materials are widely investigated for the controllable, safe and precise delivery of NGF. This review illustrates physiological and therapeutic effects of NGF for various diseases. Moreover, new progress in production and delivery technologies for NGF are summarized. Bottlenecks encountered in the development of NGF as therapeutics are also discussed with the countermeasures proposed.