LL-37

Common side effects:

• Injection site erythema and localized irritation
• Mild, transient localized swelling
• Pruritus (itching) at the administration site
• Temporary localized pain or tenderness
• Mild systemic fatigue during initial dosing

Rare or serious side effects:

• Exacerbation of certain autoimmune conditions like rosacea
• Unintended pro-inflammatory responses in specific tissues
• Potential promotion of NETosis-related tissue damage (Radic et al., 2022)
• Severe allergic reactions or anaphylaxis

Direct pathogen neutralization represents the primary mechanism of the LL-37 peptide, achieved through its amphipathic alpha-helical structure. Upon encountering microbial membranes, the positively charged peptide binds to negatively charged pathogen surfaces, inserting itself to form transmembrane pores that cause cellular leakage and death. This physical disruption effectively bypasses traditional antibiotic resistance mechanisms, making it highly effective against resilient biofilms (Memariani et al., 2023).\n\nReceptor-mediated immune modulation constitutes the secondary, yet equally critical, function of LL-37. The peptide interacts with various cell surface receptors, including FPR2, to stimulate chemotaxis, angiogenesis, and the release of immunomodulatory cytokines. Furthermore, it actively participates in NETosis—the formation of neutrophil extracellular traps—which helps contain infections but requires strict regulation to prevent tissue damage (Radic et al., 2022).

The discovery of LL-37 stems from early research into human innate immunity, where it was identified as the C-terminal peptide cleaved from the human CAP18 protein (hCAP18). As the only known human cathelicidin, it is naturally produced by neutrophils, epithelial cells, and macrophages in response to infection or injury. Endogenous production is heavily influenced by Vitamin D levels, a relationship explored in numerous clinical trials investigating Vitamin D supplementation for conditions like tuberculosis and ICU recovery (NCT00788320; NCT01372995).\n\nClinical development milestones have increasingly focused on harnessing LL-37 benefits for targeted therapeutic applications, particularly in wound healing and periodontitis (He et al., 2025). Despite promising phase 2 trials, such as those evaluating topical creams for diabetic foot ulcers (NCT04098562), the synthetic LL-37 peptide remains strictly designated for research purposes. Regulatory agencies have not yet approved it for human medical use, necessitating further investigation into its long-term safety and optimal delivery methods.