LL-37

LL-37 is not a designer peptide. It is a component of human innate immunity: the sole cathelicidin in our species, released by proteinase 3 cleavage of the precursor protein hCAP18, and produced mainly by neutrophils, keratinocytes and mucosal epithelial cells. The mature 37-residue peptide is cationic and amphipathic, folding into an alpha helix that inserts into the negatively charged membranes of bacteria and disrupts them. Vitamin D upregulates its expression, which is one of the more concrete mechanisms behind the link between vitamin D status and infection risk.

Its antimicrobial activity is broad, covering Gram-positive and Gram-negative bacteria, some fungi and enveloped viruses, and it retains activity against biofilms, which conventional antibiotics often do not. A 2023 review in World Journal of Microbiology and Biotechnology surveyed the antibiofilm literature in detail. But describing LL-37 as an antibiotic undersells and misdescribes it. Much of its physiological importance is immunomodulatory: it recruits neutrophils, monocytes and T cells, neutralises lipopolysaccharide, promotes angiogenesis and re-epithelialisation, and shapes the balance between inflammation and resolution. A 2015 review in BioFactors covers these unique features well [3].

The clinical evidence base is narrow but real, and it is topical. A 2014 randomised placebo-controlled trial published in Wound Repair and Regeneration reported that treatment with LL-37 was safe and effective in enhancing the healing of hard-to-heal venous leg ulcers [1]. A larger multicentric randomised placebo-controlled trial published in the same journal in 2021 followed up on that finding [2]. These are proper trials with placebo control and registered protocols, which is more than almost any other peptide in this category can claim, and it is the reason LL-37 sits at tier 3 rather than lower. It is worth being precise about what they show: local application to a chronic wound bed, in a specific patient population, with modest effect sizes and results that were not uniform between the two studies.

There is no human trial of systemic LL-37 for anything. There is no oral bioavailability, since a 37-residue peptide is digested. There is no established injectable dose, no pharmacokinetic profile for systemic administration, and no data on what happens to circulating immune function when exogenous cathelicidin is added to a system that regulates its own tightly.

That last point is where LL-37 diverges sharply from most peptides discussed on this site, because the risk is not hypothetical. LL-37 is an established autoantigen. In psoriasis, LL-37 forms complexes with self-DNA and self-RNA released from damaged keratinocytes, and these complexes activate plasmacytoid dendritic cells through TLR9 and TLR7, driving a type I interferon response. LL-37-specific T cells have been identified in psoriasis patients, and a 2016 study in the Journal of Investigative Dermatology characterised the binding of LL-37 to HLA-C*06:02, the principal psoriasis risk allele [4]. Related mechanisms have been implicated in rosacea, in systemic lupus erythematosus, and in the T-cell response to LL-37 seen in acute coronary syndrome and atherosclerotic plaque. Administering more of a molecule that functions as an autoantigen to someone with, or genetically predisposed to, one of these conditions is not a theoretical concern; it is an inversion of what the biology suggests.

There is also direct host toxicity at concentration. The membrane-disrupting property that kills bacteria is not perfectly selective. A 2025 study in Biochimica et Biophysica Acta Biomembranes reported that LL-37 rapidly disrupted colonic epithelial integrity in vitro [5], and older work has documented cytotoxicity to various mammalian cell types above certain thresholds. LL-37 has also been studied extensively in cancer biology, where its role is context-dependent and appears tumour-promoting in some settings and suppressive in others, another reason to be cautious about systemic exposure.

A 2025 review in Archives of Immunology and Therapeutic Experimentalis is a useful current summary of this two-sided picture, spanning pathogenesis, treatment and diagnosis [6].

Our position: LL-37 is scientifically important and clinically interesting, but the interest is concentrated in local applications, principally chronic wounds and antibiofilm strategies, where delivery is controlled and exposure is confined. Systemic use by consumers has no supporting evidence and a specific, well-documented immunological hazard. Anyone with psoriasis, rosacea, lupus or another autoimmune condition should regard exogenous LL-37 as contraindicated rather than merely unproven.