Brain delivery of lipid nanoparticles with shuttle peptides.

Lipid nanoparticles (LNPs) have gained growing attention as advanced drug delivery systems capable of addressing major challenges in the development of innovative therapies. They have been widely investigated to overcome the challenges of development delivery strategies for the Central Nervous System (CNS). Their small size, biomimetic lipid composition, and modifiable surface properties make them promising candidates for targeting the Blood Brain Barrier (BBB), leading to improved therapeutic interventions. This chapter provides an integrative overview of the main classes of LNPs and their manufacturing methods, offering insights into their design, characterization, and optimization for brain delivery. We first discuss the key physicochemical parameters -particle size, polydispersity index, surface charge, shape, crystallinity, and encapsulation efficiency- and their impact on biodistribution, stability, and BBB penetration. Formulation and manufacturing strategies are examined, from conventional approaches to microfluidic mixing. Special attention is given to surface modification strategies, including ligand conjugation and the technological variables influencing receptor-specific transport that determine brain targeting. We place particular emphasis on brain-shuttle peptides, which constitute the most widely employed approach for functionalizing LNPs. Finally, we summarize representative preclinical studies, emerging clinical trials, and key translational challenges -such as neurotoxicity, batch-to-batch reproducibility, and regulatory hurdles-, but also highlight the proved potential of LNPs to achieve successful clinical translation in other therapeutic areas. These advances provide valuable insights and technical precedents that may benefit the development of LNP-based therapeutics for CNS disorders, supporting future strategies targeting neurological and psychiatric disorders as well as brain tumors.