LL-37 is a natural human peptide that kills many germs, but it’s pricey, breaks down quickly in the body, and can hurt our own cells. Scientists are tweaking its structure, adding protective carriers, and pairing it with regular antibiotics to make it safer, more stable, and better at breaking down tough bacterial films. The review shows these tweaks work in labs, but the stuff isn’t yet ready for everyday use and still faces cost and safety hurdles.

The human antimicrobial peptide LL-37 exhibits broad antimicrobial efficacy. However, it has several limitations including high production costs, reduced efficacy under physiological conditions, susceptibility to proteolytic degradation and significant toxicity to human cells. Recent research has improved the clinical potential of peptide LL-37 through multiple systematic modifications. Therefore, we review the various modification techniques for LL-37 and explore the structure-activity relationships that underpin its antimicrobial properties. We also highlight the benefits of LL-37 derivatives and investigate their mechanisms of action against bacterial infections, particularly their effects on biofilms and cell membranes. Furthermore, we review the antimicrobial applications of LL-37 derivatives, examine nanocarrier systems for their delivery, and highlight the potential synergy between these derivatives and traditional antibiotics. Finally, it assesses the status of LL-37 derivatives in clinical applications, identifies ongoing challenges, and provides insights into future modifications and potential applications. This review aims to offer valuable strategies for enhancing LL-37 derivatives and facilitating their transition from laboratory research to clinical practice.