Antimicrobial peptides for central nervous system infections: potential of nose-to-brain delivery and current challenges

Antimicrobial resistance (AMR) in central nervous system (CNS) infections remains one of the major therapeutic challenges, as conventional antibiotics often fail to achieve adequate brain exposure. Antimicrobial peptides (AMPs) are attractive candidates because of their broad-spectrum activity and low propensity to induce resistance; however, their clinical translation is limited by proteolytic instability, cationic toxicity, and poor blood–brain barrier (BBB) permeability. This review examines intranasal (IN) nose-to-brain (N-to-B) delivery as a non-invasive strategy to enable direct CNS targeting of AMPs. We outline the anatomical basis of nasal transport, the main formulation approaches, including nanocarriers (NCs), mucoadhesive hydrogels, and dry powders, and the role of surface engineering in improving peptide stability, mucosal residence, and neuronal uptake. Preclinical evidence from peptide delivery systems supports the feasibility of this route, but dedicated in vivo studies in CNS infection models are still missing. Safety, scalability, regulatory constraints, and dose reproducibility remain key translational barriers. Overall, an integrated strategy combining peptide engineering with advanced delivery platforms may accelerate the development of IN AMP-based therapies for resistant CNS infections.