Polymeric nanoparticles functionalized with peptides: Advanced strategies for crossing the blood-brain barrier

Targeted drug delivery to the central nervous system (CNS) to tackle brain disorders is hindered by the blood-brain barrier (BBB) which, due to its unique physiology, severely restricts the entry of drugs into the brain. Among the different strategies proposed to overcome the BBB, nanotechnology-based approaches, particularly polymeric nanoparticles (PNPs), have emerged as promising tools. These carriers can protect therapeutic payloads, modulate release profiles, and enhance drug concentration in the CNS. Furthermore, their surfaces can be functionalized with brain shuttle peptides for active targeting strategies. Peptide shuttles recognize specific receptors on the cerebral endothelium, thereby promoting transcytosis and facilitating selective transport into the brain. Peptides functionalizing the surface of PNPs may also increase the interactions between these PNPs and lipid bilayers thereby improving their penetration across the BBB. This chapter discusses the properties and design of peptide-functionalized PNPs, emphasizing how particle size, surface and biodegradability critically influence their performance. Chemical conjugation methods enabling the stable attachment of peptide shuttles are discussed, with particular attention to translational studies addressing major CNS pathologies, including brain tumors, neurodegenerative diseases, and ischemic injuries. Current challenges that determine clinical application, such as variability in synthesis, toxicity, and enzymatic instability, are also critically analysed with the aim of outlining future directions for peptide-mediated drug delivery to the brain.