Thymosin Alpha-1 vs. LL-37: Immune Peptides
Thymosin Alpha-1 (TA1) and LL-37 both fall under the broad heading of "immune peptides," but the similarity is deceptive. One is a thymus-derived immunomodulator that tunes the adaptive immune system from the inside.
Thymosin Alpha-1 (TA1) and LL-37 both fall under the broad heading of "immune peptides," but the similarity is deceptive. One is a thymus-derived immunomodulator that tunes the adaptive immune system from the inside. The other is a frontline antimicrobial weapon that punches holes in bacterial membranes and rallies inflammatory reinforcements.
Comparing them is a bit like comparing a general who coordinates troop movements to a soldier who fights hand-to-hand. Both matter for defense. They just operate on entirely different scales and through entirely different mechanisms.
This guide breaks down what each peptide does, how it does it, where the clinical evidence stands, and who might benefit from which approach. For deeper dives on either peptide individually, see our Thymosin Alpha-1 guide and LL-37 profile.
Origins and Basic Biology
Thymosin Alpha-1: A Signal From the Thymus
TA1 is a 28-amino-acid peptide originally isolated from calf thymus tissue in the 1970s by Dr. Allan Goldstein and colleagues at the George Washington University. The thymus gland produces it naturally as part of the process that trains and matures T cells. As the thymus shrinks with age -- a process called thymic involution -- endogenous TA1 levels decline, which tracks closely with age-related immune deterioration.
The synthetic version, marketed as Zadaxin (thymalfasin), is a biologically identical copy of the natural peptide. It has a molecular weight of approximately 3 kilodaltons and adopts a partially helical conformation, with a stable alpha-helix region spanning residues 14 through 26.
LL-37: The Body's Built-In Antibiotic
LL-37 is a 37-amino-acid peptide and the only member of the cathelicidin family found in humans. Its name comes from its two leading leucine residues and its length. The peptide is derived from the precursor protein hCAP18 (human cationic antimicrobial protein of 18 kDa), which is cleaved by proteinase 3 to release the active LL-37 fragment.
Unlike TA1, which comes from a single gland, LL-37 is produced across multiple tissue types. Neutrophils store it in specific granules. Epithelial cells lining the skin, gut, lungs, and urinary tract synthesize it in response to infection or injury. Macrophages, lymphocytes, and mast cells all contribute to local LL-37 production as well.
The peptide carries a net positive charge of +6, which is central to how it works. It is amphipathic -- one side is hydrophobic, the other hydrophilic -- allowing it to interact with and disrupt negatively charged microbial membranes while largely sparing host cells.
One detail worth noting: LL-37 expression is regulated in part by vitamin D. When vitamin D binds its receptor in immune cells, it upregulates transcription of the cathelicidin gene. This is one reason vitamin D deficiency has been linked to increased susceptibility to infections -- the body literally produces less of its primary antimicrobial peptide. LL-37 belongs to an ancient class of host defense peptides found across vertebrate species. Cathelicidins have been identified in cattle, pigs, horses, rabbits, and fish, though LL-37 is the sole human representative. This evolutionary conservation hints at how fundamental these peptides are to innate immunity.
Mechanisms of Action: Where They Diverge
This is where the two peptides part ways most dramatically. TA1 operates primarily as an immune system coordinator. LL-37 operates primarily as a direct-action antimicrobial agent. Both have secondary functions that blur these lines, but the primary mechanisms are distinct.
How Thymosin Alpha-1 Works
TA1 functions as a Toll-like receptor (TLR) agonist, primarily targeting TLR9 and TLR2 on myeloid and plasmacytoid dendritic cells. When it binds these receptors, it activates the MyD88-dependent signaling pathway, triggering downstream cascades that include p38 MAPK, NF-kB, and TRAF6. The result is a coordinated upregulation of immune-related gene expression.
Here is what that looks like in practice:
Dendritic cell maturation. TA1 increases expression of MHC Class I and II molecules along with co-stimulatory molecules like CD40 and CD80. This shifts immature dendritic cells from an antigen-capturing state into professional antigen-presenting cells capable of activating T cell responses. In certain contexts, it also induces the enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid dendritic cells, activating tryptophan catabolism pathways that maintain immune tolerance and prevent runaway inflammation.
T cell effects. TA1 promotes differentiation of T cell progenitors into mature CD4+ helper and CD8+ cytotoxic T cells. It pushes the balance toward Th1 responses, increasing production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2). Through the IDO pathway, it also expands regulatory T cells (CD4+CD25+FoxP3+ Tregs), which check excessive immune activation. Some research suggests it can downregulate the exhaustion marker PD-1 on T cells while upregulating activation markers like CD40L.
NK cell activation. TA1 boosts natural killer cell cytotoxic activity, adding another layer to anti-viral and anti-tumor surveillance.
The net effect is what researchers have called an immune "rheostat" -- TA1 can simultaneously boost defenses against pathogens and tumors while dampening excessive inflammation. It restores balance rather than simply pushing the immune system in one direction. For more on this evidence, see our TA1 clinical evidence review.
How LL-37 Works
LL-37 takes a fundamentally different approach. Its primary mechanism is direct killing of microorganisms through membrane disruption.
Membrane attack. The peptide's positive charge draws it toward the negatively charged surfaces of bacterial membranes -- specifically lipopolysaccharides (LPS) in Gram-negative bacteria and teichoic acids in Gram-positive species. Once bound, LL-37 adopts an alpha-helical conformation and inserts itself into the lipid bilayer.
Researchers have proposed multiple models for what happens next. The "toroidal pore" model suggests LL-37 induces curvature strain in the membrane, creating temporary aqueous channels that leak ions and metabolites until the cell dies. The "carpet" model proposes that above a certain concentration threshold, the peptide orients parallel to the membrane surface and dissolves it like a detergent. Recent biophysical work suggests the actual mechanism may be lipid-dependent: LL-37 can form protective fiber structures in saturated lipid environments while forming destructive pores in unsaturated or cholesterol-containing membranes. Beyond membrane damage, the peptide can enter cells and bind directly to DNA and RNA, disrupting transcription and translation.
Antibiofilm activity. LL-37 is effective against bacterial biofilms -- communities of bacteria encased in protective matrices that resist conventional antibiotics. Studies have demonstrated activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Staphylococcus epidermidis biofilms, at concentrations that are often sub-inhibitory for planktonic (free-floating) bacteria. For broader context on antimicrobial peptides and their role against resistant infections, see our antimicrobial peptides research overview.
Immune modulation. LL-37 also has immunomodulatory functions, though they differ qualitatively from TA1's. It neutralizes bacterial LPS, which prevents overactivation of TLR4 and helps control the cytokine storm that drives sepsis. Simultaneously, it acts as a chemokine, attracting neutrophils, monocytes, and T cells to infection sites. It stimulates IL-8 release from keratinocytes and macrophages. One notable and sometimes problematic function: LL-37 can form complexes with self-DNA and self-RNA to activate plasmacytoid dendritic cells through TLR9 and TLR7 -- a process implicated in autoimmune conditions like psoriasis and lupus.
Wound healing. LL-37 promotes re-epithelialization by stimulating keratinocyte migration and proliferation via transactivation of the epidermal growth factor receptor (EGFR). It induces angiogenesis through endothelial cell activation and promotes fibroblast proliferation and collagen matrix organization. This makes it part of the body's repair toolkit, not just its defense arsenal. Our LL-37 research overview covers these wound healing pathways in more detail.
Clinical Evidence: What Has Been Tested in Humans?
Thymosin Alpha-1: Decades of Clinical Data
TA1 has one of the longer clinical track records of any peptide therapeutic. Zadaxin is approved in more than 35 countries -- across Asia-Pacific, Latin America, and the Middle East, including China, India, Singapore, Argentina, Peru, and Mexico. In the United States, the FDA has granted it Orphan Drug Designation for malignant melanoma, chronic active hepatitis B, and hepatocellular carcinoma, though it is not broadly approved for general use.
Hepatitis B. This is the most extensively studied indication. Randomized controlled trials have demonstrated that TA1 can inhibit viral replication and normalize liver enzyme levels (ALT). One trial found a 42.3% complete response rate at six-month follow-up compared to 23.3% for interferon alpha. Notably, the responses tend to be durable -- continuing and sometimes improving after treatment ends, unlike some antiviral therapies where relapse is common upon discontinuation. TA1 is frequently combined with antivirals like lamivudine or entecavir to improve both biochemical and virologic response.
Hepatitis C. Trials have examined TA1 as an add-on to interferon-based regimens. One study reported sustained biochemical response in 22.4% of patients receiving combination therapy versus 9.3% with interferon alone. In difficult-to-treat non-responders, adding TA1 to pegylated interferon and ribavirin ("triple therapy") increased sustained virological response rates from 26.3% to 41.0%.
Cancer. TA1 is studied primarily as an immunological adjuvant to chemotherapy rather than a standalone cancer treatment. Post-operative use in HBV-related hepatocellular carcinoma has shown improvements in overall survival and recurrence-free survival. In non-small cell lung cancer, studies suggest it may reduce chemoradiation-induced lymphopenia. Phase II and III trials have evaluated its immunomodulatory effects in melanoma.
COVID-19 and sepsis. During the pandemic, TA1 attracted attention as a potential immunomodulator for severe COVID-19, with clinical trials registered at ClinicalTrials.gov. Its dual ability to boost antiviral immunity while restraining hyperinflammation made it a logical candidate. Earlier sepsis research had already demonstrated potential for reducing mortality in critically ill patients.
Safety. Across thousands of patients in clinical trials, TA1 has demonstrated a favorable safety profile. The most commonly reported adverse event is mild injection site irritation. The peptide has essentially no drug-related side effects in most published studies -- a notable contrast to interferon-based therapies, which commonly cause flu-like symptoms, fatigue, and depression.
LL-37: Earlier-Stage but Promising
LL-37's clinical evidence is considerably thinner than TA1's. Most data come from preclinical models, with only a handful of human studies completed.
Wound healing. The most advanced clinical work involves chronic venous leg ulcers. A Phase I/II randomized controlled trial by Pergamum AB demonstrated that topical LL-37 at low-to-medium doses (0.5 and 1.6 mg/mL) significantly improved healing rates, with the 0.5 mg/mL dose increasing the healing rate constant sixfold compared to placebo. The treatment was confirmed safe for human use. A subsequent larger study (2021) produced mixed results: no significant improvement in the overall study population, but post hoc analysis revealed benefits for patients with wounds larger than 10 square centimeters. Randomized trials are also underway testing LL-37 cream for diabetic foot ulcers.
Sepsis and infections. In mouse and rat models of sepsis using cecal ligation and puncture, LL-37 administration significantly improved survival by suppressing macrophage pyroptosis (a form of inflammatory cell death) and reducing bacterial load. A 2024 study demonstrated that LL-37 protects against sepsis-induced acute lung injury by inhibiting the NLRP3-caspase1 pyroptotic pathway. These are promising preclinical findings, but human sepsis trials with LL-37 have not yet been reported.
Antimicrobial activity. Lab studies demonstrate broad-spectrum killing of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. LL-37 shows synergy with polymyxin B against multidrug-resistant bacteria and biofilms. It can eliminate intracellular S. aureus hiding within osteoblasts more effectively than many conventional antibiotics -- a finding relevant to chronic bone infections. For related peptide research, see our defensins overview.
Challenges. Several obstacles stand between LL-37 and widespread clinical use. The peptide degrades rapidly in biological fluids due to protease activity. At high concentrations it can be cytotoxic to host cells, causing hemolysis and leukocyte damage. Production costs are substantial for a 37-amino-acid peptide. Researchers are developing protease-resistant analogs (such as D-LL-37, built from D-amino acids) and novel delivery systems like chitosan hydrogels and extracellular vesicles to address these limitations.
Head-to-Head Comparison
| Feature | Thymosin Alpha-1 | LL-37 |
|---|---|---|
| Length | 28 amino acids | 37 amino acids |
| Origin | Thymus gland | Neutrophils, epithelial cells, macrophages |
| Primary function | Immunomodulation | Direct antimicrobial killing |
| Key receptors | TLR2, TLR9 | Microbial membranes; EGFR; FPRL-1 |
| Mechanism | Dendritic cell maturation, T cell activation, NK cell boost | Membrane disruption, biofilm destruction, chemokine activity |
| Immune effect | Bidirectional (boosts and restrains) | Primarily pro-inflammatory; LPS neutralization |
| Wound healing | Not a primary function | Yes -- keratinocyte migration, angiogenesis |
| Clinical stage | Approved in 35+ countries | Phase I/II trials (topical wound healing) |
| Safety profile | Excellent; minimal side effects | Good at therapeutic doses; cytotoxic at high concentrations |
| Administration | Subcutaneous injection (1.6 mg, twice weekly typical) | Topical or subcutaneous (research protocols vary) |
| Main studied indications | Hepatitis B/C, cancer adjuvant, sepsis | Chronic wounds, infections, biofilms |
When Would You Choose One Over the Other?
These peptides are not really competitors. They address different problems through different biological pathways, which means the choice depends entirely on what you are trying to accomplish.
TA1 is better studied for systemic immune modulation. If the goal is to restore compromised immune function -- in chronic viral infections, as an adjunct to cancer immunotherapy, in immunosenescence, or in situations requiring balanced immune activation without excessive inflammation -- TA1 has both the mechanistic rationale and the clinical evidence. Its approval in over 35 countries for hepatitis B reflects decades of safety and efficacy data.
LL-37 is more relevant to local infections and wound healing. If the problem is a drug-resistant wound infection, a chronic biofilm, or a situation requiring both antimicrobial action and tissue repair at the same site, LL-37's dual antimicrobial and wound healing properties make it the more logical choice. However, the clinical evidence is still maturing, with most data from preclinical models or early-phase trials.
There is also a theoretical case for combining both approaches -- using TA1 to optimize systemic immune coordination while deploying LL-37 locally to clear infections and promote healing. No clinical trials have tested this combination, but the non-overlapping mechanisms suggest they could be complementary.
What We Still Do Not Know
Both peptides have significant gaps in the research record.
For TA1, the biggest question is why it has not achieved FDA approval in the United States despite its global track record and positive trial data. The U.S. regulatory pathway has proven challenging, and some researchers argue that larger, more rigorously designed Phase III trials are needed. There is also uncertainty about the optimal dosing for different conditions and whether TA1's immunomodulatory effects extend meaningfully to healthy individuals with intact immune function.
For LL-37, the translational gap between laboratory success and clinical utility remains wide. Proteolytic degradation in biological fluids is a persistent problem. The concentration-dependent toxicity creates a narrow therapeutic window for systemic use. The link between LL-37 and autoimmune conditions like psoriasis raises safety questions that will need careful monitoring in long-term studies. And the mixed results from the 2021 venous leg ulcer trial -- where overall population outcomes fell short despite subgroup benefits -- suggest that identifying the right patient population will be as important as optimizing the peptide itself.
There is also a broader question about how these peptides fit into the evolving regulatory environment. The FDA's 2024 actions on peptide compounding have affected access to several peptides in the United States, and both TA1 and LL-37 exist in a complex space between research compound, pharmaceutical product, and compounded medication. How regulators ultimately classify and control these molecules will shape their availability for years to come.
The Bottom Line
Thymosin Alpha-1 and LL-37 represent two fundamentally different strategies within the immune peptide space. TA1 is the coordinator -- modulating dendritic cells, shaping T cell responses, and maintaining the balance between immune activation and restraint. LL-37 is the first responder -- killing bacteria on contact, tearing apart biofilms, recruiting immune cells to the scene, and jumpstarting tissue repair.
TA1 has the deeper clinical evidence base, with regulatory approvals across dozens of countries and decades of human safety data. LL-37 has the broader biological activity profile but is still in the early stages of clinical translation. Neither replaces the other.
For anyone considering immune peptides, understanding this distinction matters. The right choice depends on whether the problem is systemic immune dysfunction or local infection and tissue damage. In many real-world scenarios, the answer may ultimately be both.
For a broader look at peptides that support immune function, see our guide to the best peptides for immune support.
This article is for educational purposes only. It does not constitute medical advice. Consult a qualified healthcare provider before making decisions about peptide therapies.