LL-37 is a natural human peptide that can kill microbes and influence the immune system, but using it as a drug is hard because it breaks down quickly, can be toxic, and is expensive to make. Scientists are tweaking its structure—making shorter versions, flipping the sequence, or attaching it to tiny carriers—to make it more stable, less harmful, and cheaper. These engineered versions look promising for future medicines, but they’re still in the research stage.

Cathelicidins are a family of antimicrobial peptides (AMPs) with broad-spectrum activity and immunomodulatory functions. Among them, the only human cathelicidin LL-37 has garnered significant interest due to its potent antimicrobial, antiviral, antifungal, antiparasitic, and antitumor properties. However, the clinical application of LL-37 is hindered by several limitations, including low proteolytic stability, cytotoxicity, and high production costs. To overcome these challenges, a wide range of design strategies have been employed to modify LL-37 and improve its therapeutic potential. LL-37-based analogs represent promising candidates for the development of next-generation antimicrobial and immunomodulatory therapies. Despite significant progress, further research is required to optimize peptide design, ensure cost-effective production, and validate long-term safety and efficacy. Advances in computational modeling, high-throughput screening, and nanotechnology will play an important role in the translation of modified cathelicidins into clinical practice. This review summarizes key strategies of chemical and structural modifications of LL-37 aimed at enhancing its functional properties. Particular attention is given to truncated and retro-analogs, which preserve or improve biological activity while exhibiting reduced toxicity and increased proteolytic resistance. Furthermore, we highlight the use of nanoscale delivery systems, which facilitate targeted delivery, prolong peptide half-life, and mitigate cytotoxic effects.