Intranasal delivery of glucagon-like peptide-1 to the brain for obesity treatment: opportunities and challenges

Abstract

ABSTRACT Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), approved by the US FDA for obesity treatment, are typically administered subcutaneously, an invasive method leading to suboptimal patient adherence and peripheral side effects. Additionally, this route requires the drug to cross the restrictive blood–brain barrier (BBB), limiting its safety and effectiveness in weight management and cognitive addiction disorders. Delivering the drug intranasally could overcome these drawbacks. Areas covered This review summarizes GLP-1 RAs used as anti-obesity agents, focusing on the intranasal route as a potential pathway to deliver these biomolecules to the brain. It also discusses strategies to overcome challenges associated with nasal delivery. Expert opinion Nose-to-brain (N2B) pathways can address limitations of the subcutaneous route for GLP-1 RAs. However, peptide delivery to the brain is challenging due to nasal physiological barriers and the drug’s physicochemical properties. Innovative approaches, such as cell permeation enhancers, mucoadhesive systems, and nanocarriers in nasal formulations, along with efficient drug delivery devices, show promising preclinical results. Despite this, successful preclinical data does not guarantee clinical effectiveness, highlighting the need for comprehensive clinical investigations to optimize formulations and fully utilize the nose-to-brain interface for peptide delivery.