Engineering chitosan functionalized extracellular vesicles for targeted brain gene delivery and neurotherapeutics

Gene therapy represents a crucial frontier in modern medicine for brain diseases; however, a significant obstacle hinders its progress. The immense difficulty of therapeutic molecules that deliver to the brain should be in a safe and effective way. The challenge is that blood brain barrier (BBB) blocks most drugs from entering. Exosomes offer a powerful solution to this problem due to their innate ability to cross this barrier and biocompatibility that makes them exceptional platforms for gene delivery. This article provides a detailed analysis of the latest methods for engineering these exosomes with a specific emphasis on chitosan. Chitosan possesses unique properties that can enhance exosome function. The authors introduce a clear framework to organize and understand this chitosan engineered exosomal systems. This framework categorizes them based on key features like their design architecture, the type of genetic cargo they carry, their specific targeting mechanisms and their stage of development toward clinical use. The review also offers a comparative analysis of preclinical animal studies to assess the therapeutic potential, limitations and progress of these systems toward human trials. It further covers innovative techniques that leverage chitosan to improve critical steps in the exosome workflow. These steps include the isolation and purification of exosomes, the efficient loading of drug/gene cargo and the precision targeting of brain tissue. Evidence from these preclinical models demonstrates that exosomes modified with chitosan achieve superior gene transfer efficiency and produce stronger neuroprotective outcomes compared to unmodified versions. This review outlines the current challenges that block the path to clinical applications. These challenges include scalable manufacturing and long-term safety studies. The goal is to advance chitosan based exosomal gene therapy from a promising concept into a viable and standardized treatment for a range of neurological diseases. Graphical Abstract