CAQK

What is CAQK?

CAQK is a tetrapeptide — cysteine, alanine, glutamine, lysine — identified by Erkki Ruoslahti's group at Sanford Burnham Prebys as a homing peptide for acute central nervous system injury. Injected systemically, it accumulates selectively at sites of brain and spinal cord damage while largely sparing healthy tissue, because injury exposes and upregulates an extracellular matrix target that intact tissue does not present. What that target is has been revised, and the revision matters because most secondary descriptions still carry the old version. The 2016 origin paper identified the binding partner as a chondroitin sulfate proteoglycan complex, with versican core protein and hyaluronan and proteoglycan link protein 4 appearing exclusively in CAQK affinity eluates. The 2025 follow-up from the same group tested that directly and overturned the glycosaminoglycan interpretation: stripping chondroitin and dermatan sulfate chains with chondroitinase ABC 'had no effect on the FAM-CAQK binding', from which they concluded that 'CAQK interacts with a protein, not a glycosaminoglycan, in the CSPG complex'. Proteomics identified that protein as tenascin-C, with binding localised to its fibronectin type III domains 5 and 6. Earlier versions of this page described CAQK as binding chondroitin sulfate proteoglycans; the accurate statement is that it binds tenascin-C within a proteoglycan complex. For almost its entire history CAQK has been a delivery vehicle rather than a drug. The 2024 systematic review found that of sixteen qualifying studies, 'All studies except one used CAQK to deliver a therapeutic agent' and 'No studies directly evaluated the effects of CAQK alone.' That changed in 2025, when the originating group reported that unconjugated CAQK itself reduced lesion size and improved function in injured mice — a genuinely new claim, from the group that stands to benefit from it.

What CAQK Is Investigated For

CAQK's established role is as an address label. Across more than a dozen independent groups it has been attached to liposomes, exosomes and extracellular vesicles, polymer micelles, porous silicon nanoparticles, engineered mitochondria and PEG conjugates, and used to steer cargo into traumatic brain injury, spinal cord injury, demyelinating lesions, ischaemic stroke and subarachnoid haemorrhage models. The 2016 origin paper's most striking result still stands as the clearest demonstration of what targeting buys: CAQK-coated nanoparticles carrying silencing oligonucleotides produced the first evidence of gene silencing in injured brain parenchyma from systemically administered siRNA. That is a delivery problem the field had not solved. The newer and more fragile claim is that CAQK is therapeutic by itself. A 2025 EMBO Molecular Medicine paper reported that intravenous unconjugated CAQK after moderate or severe TBI in mice reduced injury size, apoptosis and inflammatory markers and improved functional deficit, with no overt toxicity — and proposed a mechanism, since tenascin-C binding at the FN(III)5-6 domains is where the receptor contactin-1 docks, so CAQK may act as a competitive block on a pro-inflammatory signalling axis. A 2026 rat spinal cord injury study from a partly overlapping group reported similar motor benefit. Two caveats bound this. First, the therapeutic evidence is two papers, both involving the originating group, against a delivery literature that is large and genuinely independent. Second, the pig data are frequently overstated, including by an earlier version of this page: pigs received fluorescent CAQK and were used to establish homing and a roughly 30-minute blood half-life, with no treatment arm and no functional outcome. Every efficacy result is in rodents.

History & Discovery

CAQK came out of Erkki Ruoslahti's long programme on tissue-homing peptides at Sanford Burnham Prebys, the same line of work that produced the RGD and CendR targeting motifs. The method was in vivo phage display: inject a library of cyclic peptides into an animal with a specific pathology, recover what sticks, and sequence it. In this case a T7 library displaying 9-amino-acid cyclic peptides was injected 6 hours after a penetrating stab-wound brain injury in mice, and the winning motif was pared down to four residues. The 2016 Nature Communications paper established the core properties: selective binding to injured mouse and human brain, systemic homing to injury sites, and — the result that mattered most — the ability to carry cargo ranging from small molecules to nanoparticles, including the first demonstration of gene silencing in injured brain parenchyma from systemically administered siRNA. Over the following decade the peptide was adopted widely as a targeting moiety by groups with no connection to the originating lab, in China, Iran, Canada, Singapore and elsewhere, across traumatic brain injury, spinal cord injury, multiple sclerosis models, stroke and subarachnoid haemorrhage. The second chapter began in 2025 with two revisions of the original account. The target turned out not to be the glycosaminoglycan component everyone had been citing but tenascin-C, a protein within the same complex, bound at its fibronectin type III domains 5 and 6. And the peptide itself, given unconjugated, reduced lesion size and improved function in injured mice — converting a delivery tool into a drug candidate. The same paper extended homing into pigs, establishing that a large animal handles the peptide appropriately, with a blood half-life around 30 minutes. Commercially, the asset sits with AivoCode, a San Diego company spun out of Sanford Burnham Prebys. Its competing-interest disclosures are explicit: the senior authors are inventors on the patents and are founders, officers and equity holders. The programme has drawn a series of SBIR awards since 2016, including an NIH Phase II grant supporting the chemistry, manufacturing and non-GLP toxicology needed for an IND filing, with that period ending in March 2026. The honest summary of where that leaves things is pre-IND and capital-constrained: GLP toxicology unreported, no IND filed, no trial registered, and the company's own public framing making human work conditional on both positive large-animal results and additional funding.

How It Works

After a brain or spinal cord injury, the damaged tissue starts displaying proteins that healthy tissue keeps hidden. CAQK is a very short peptide that sticks to one of them — tenascin-C. Injected into a vein, it circulates everywhere but only stays where that protein is exposed, which means at the injury. Attach a drug or a nanoparticle to it and the cargo goes where the damage is instead of being spread through the whole body.

CAQK was found by in vivo phage display: a T7 library displaying 9-amino-acid cyclic peptides was injected intravenously 6 hours after a penetrating stab-wound brain injury in mice, and phage recovered from injured tissue was sequenced and the active motif truncated to the CAQK tetramer. The controlled cortical impact model frequently cited as the discovery setting was in fact a later cross-validation, used to confirm that homing generalised to a different injury type. The binding target was revised in 2025 and the revision is the most important mechanistic content on this page. Affinity work in 2016 pulled down a lectican chondroitin sulfate proteoglycan complex — versican core protein and hyaluronan and proteoglycan link protein 4 were exclusive to CAQK eluates, with tenascin-R also present but appearing in the control as well. That led to a decade of describing CAQK as a CSPG-binding peptide. The 2025 experiment removed the sugar: chondroitinase ABC digestion of chondroitin and dermatan sulfate side chains 'had no effect on the FAM-CAQK binding'. Proteomics across two independent CSPG preparations identified tenascin-C as the shared protein, CAQK bound it dose-dependently, and binding to related glycoproteins including tenascin-R was only marginal. Domain mapping narrowed the site to fibronectin type III domains 5 and 6. That localisation supplies a mechanism for the therapeutic claim rather than only the targeting one. Tenascin-C contributes to glial scarring, neuroinflammation, blood-brain barrier disruption and neuronal apoptosis, and it inhibits oligodendrocyte differentiation — and the signalling cascade responsible requires the cell-surface receptor contactin-1 to bind tenascin-C at exactly the FN(III)5-6 domains CAQK occupies. Competitive blockade at that interface is a coherent explanation for why unconjugated CAQK reduced apoptosis and inflammatory markers. The originating group offers a second, looser hypothesis as well: CAQK's free cysteine thiol could act as a reactive oxygen species scavenger or glutathione precursor in the manner of N-acetylcysteine. Neither mechanism has been tested by an independent group. Pharmacokinetically CAQK behaves as a very small peptide should. Blood half-life in pigs was about 30 minutes, which is short enough that repeated dosing is required and is why protocols give it daily for a week rather than once.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about CAQK:

• 01Any human data. No registered trial, no IND on file, no human pharmacokinetics or safety. The programme has been preclinical for a decade and remains pre-IND.
• 02Independent replication of the therapeutic claim. Homing and delivery have been reproduced by many unaffiliated groups, but both studies testing unconjugated CAQK as a neuroprotective agent involve the originating group, whose members hold the patents and have equity in the developing company. Those conflicts are disclosed; the gap is still real.
• 03Large-animal efficacy. Pig work established homing and a roughly 30-minute half-life with no treatment arm or functional outcome. The originating group describes the prerequisites for pig efficacy studies as being in place, but no such study has been reported.
• 04Whether tenascin-C binding is selective enough in a whole organism. Tenascin-C is upregulated in tumours, healing wounds and inflamed tissue generally, not only in CNS injury, and no study has characterised off-lesion distribution in an animal with a concurrent tumour or systemic inflammation.
• 05Mechanistic confirmation of the contactin-1 competition hypothesis. The proposal that CAQK blocks the contactin-1 docking site on tenascin-C FN(III)5-6 is structurally plausible and would explain the anti-inflammatory effect, but it has not been tested directly.
• 06Duration and durability. Every therapeutic protocol is 7 days; nobody has tested longer courses, delayed initiation beyond 6 hours, or whether benefit persists months after dosing stops.
• 07Comparative value against the cargo it usually carries. In most studies CAQK targets a therapeutic agent, and few designs isolate how much benefit comes from targeting versus from the drug itself delivered untargeted.

Forms & Administration

Intravenous injection in every published study — appropriate for a homing peptide, which must circulate to find its target. Mouse protocols use 200 nmol (roughly 5 mg/kg) per dose and rat protocols 2.5 mg/kg, beginning 1 to 6 hours after injury and continuing once daily for 7 days. In most of the literature CAQK is not administered alone but conjugated to a carrier — liposomes, extracellular vesicles, polymer micelles, porous silicon nanoparticles or polymer-peptide constructs. There is no human formulation, no approved product and nothing available for human use.

Dosing & Protocols

The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.

CAQK has never been administered to a human in a registered study and is not approved for any use in any jurisdiction. All dosing information here is from rodent research protocols and has no human equivalent.

Timeline of Effects

Common Questions

Who CAQK Is NOT For

Drug & Supplement Interactions

No drug-interaction studies have been published, and no human pharmacology exists against which to assess them. What follows is mechanistic reasoning, not data. The interaction space that would matter most in a real clinical setting is with agents given acutely after brain or spinal cord injury: osmotic therapy, sedatives, anticonvulsants, and in spinal cord injury historically corticosteroids. CAQK's mechanism — competitive binding at tenascin-C — has no obvious pharmacokinetic overlap with any of these, since it is a short peptide cleared within hours and not metabolised by cytochrome pathways. Corticosteroids are worth a specific mention because they suppress the inflammatory cascade CAQK is proposed to interrupt, so the two could in principle be redundant rather than additive. The more relevant consideration in the published literature is not drug interaction but cargo interaction. CAQK is usually conjugated to something, and conjugation chemistry demonstrably changes behaviour — a 2025 study specifically examined how conjugation chemistry alters the pharmacokinetics of peptide-polymer conjugates in a TBI model. The peptide's properties cannot be assumed to carry over unchanged when it is attached to a nanoparticle, and vice versa. Absence of documented interactions here reflects the complete absence of clinical pharmacology, not an established safety margin.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions