Toward non-invasive CNS delivery: The emergence of brain shuttle peptides

The blood–brain barrier (BBB) is a highly specialized interface that preserves neural homeostasis but severely limits the entry of therapeutic agents, posing a major challenge for central nervous system (CNS) drug development. While invasive approaches such as intracerebral injection and focused ultrasound can transiently bypass the barrier, their complexity and safety concerns restrict clinical applicability, particularly in chronic conditions. Non-invasive strategies that exploit endogenous transport mechanisms—carrier-mediated uptake, adsorptive-mediated transcytosis (AMT), and receptor-mediated transcytosis (RMT)—may offer a safer solution. Within this framework, brain shuttles have emerged as molecular vectors designed to cooperate with endothelial biology rather than disrupt it. These include antibodies, proteins, small molecules, and peptides, each with distinct advantages and limitations. Among them, peptides stand out for their versatility, manufacturability, and chemical tunability. Advances in solid-phase synthesis, non-natural modifications, and rational design have enabled peptides to achieve a balance between uptake efficiency and release beyond the endothelium. Their modular nature supports conjugation to diverse payloads, including small molecules, proteins, nucleic acids, and nanoparticles, while maintaining functional integrity. Peptide shuttles also offer broader receptor targeting and compatibility with multiple administration routes, positioning them as a cornerstone of future CNS delivery platforms. This chapter provides a mechanistic overview of the BBB, reviews invasive and non-invasive delivery strategies, and introduces the concept and evolution of brain shuttle peptides. It sets the stage for subsequent discussions on discovery methodologies, chemical optimization, validation models, and translational pathways, highlighting the promise of peptide-enabled systems to transform therapeutic access to the brain.