Overcoming delivery challenges of antimicrobial peptides for clinical translation: From nanocarriers to molecular modifications.

Antimicrobial peptides (AMPs) have emerged as a promising solution to combat multidrug-resistant (MDR) bacteria. Their unique mechanisms of action reduce the likelihood of resistance development. However, despite their potential, AMPs in clinical trials face significant challenges, including proteolytic degradation and short half-lives during systemic or oral administration. To address these limitations and enhance AMP stability and therapeutic efficacy, several key strategies have been explored. In this review, we summarize recent advances in AMP design, covering: 1) the delivery and formulation of AMPs, including metal-based, polymer-based, and lipid-based delivery systems, as well as the self-assembled nanotechnology of AMPs; 2) the internal modification of AMPs, including stereochemical modification, structural cyclization modification, and terminal modification. This review provides critical insights into AMP optimization, guides the development of future drug candidates, and highlights the interdisciplinary approaches required to accelerate clinical translation.