Against the backdrop of a global push toward green and sustainable agriculture, the biopesticide market is entering a period of rapid growth: the global market for biostimulants and biopesticides is projected to reach US$30 billion within the next decade. Among the emerging biopesticide technologies, plant-derived cyclotides — owing to their exceptional target specificity, environmental compatibility, and outstanding stability — are increasingly becoming a focal point for research and industry worldwide.

This overview is based on a recent comprehensive review, "Cyclotides as sustainable biopesticides: structure, function and agricultural potential" by Shambhawi, Zhang, Chan and Craik, published in Phytochemistry Reviews (2026), from the Institute for Molecular Bioscience at the University of Queensland. The review provides a systematic synthesis of cyclotide bioactivities, structure–function relationships, evolutionary origins, and agricultural application prospects, which this article draws on throughout.

1. The Distinctive Structure and Exceptional Stability of Cyclotides

Cyclotides are a family of cyclic plant peptides found natively in several plant families (including Rubiaceae, Violaceae, Cucurbitaceae, Fabaceae, Solanaceae and Loganiaceae). Their core structural features are:

• A head-to-tail cyclised backbone, which contributes to their exceptional conformational rigidity.

• A cystine knot motif (cyclic cystine knot, CCK), built from six conserved cysteine residues forming three interlocking disulfide bonds (labelled with Roman numerals I–VI in the peptide backbone).

This distinctive molecular architecture confers exceptional conformational rigidity and resistance to proteolytic, thermal, and chemical degradation. This exceptional stability greatly enhances cyclotides' resilience to formulation and storage, broadening their potential applications in agriculture and helping to overcome the degradation issues that limit many other peptide-based pesticides.

2. Broad Agricultural Bioactivity Spectrum

Research shows that cyclotides play a multifunctional role in plant innate defence. To date, a total of 36 cyclotides and five acyclotides (non-cyclised variants) obtained from plants have been studied for insecticidal, nematocidal, molluscicidal, or antimicrobial activity:

A commercial precedent: The biopesticide Sero-X, developed from an extract of Clitoria ternatea (butterfly pea) and containing over 80 cyclotides, has been approved and registered in Australia. It has demonstrated consistent field efficacy in managing Verticillium wilt in cotton, as well as against various lepidopteran and sap-sucking pests — establishing an important commercial precedent for cyclotide-based crop protection.

3. Cyclotides Compared with Other Mainstream Biopesticide Technologies

To position cyclotides within the broader landscape of sustainable crop protection, the review compares them across several dimensions with other leading biopesticide technologies:

A commercial precedent: The biopesticide Sero-X, developed from an extract of Clitoria ternatea (butterfly pea) and containing over 80 cyclotides, has been approved and registered in Australia. It has demonstrated consistent field efficacy in managing Verticillium wilt in cotton, as well as against various lepidopteran and sap-sucking pests — establishing an important commercial precedent for cyclotide-based crop protection.

3. Cyclotides Compared with Other Mainstream Biopesticide Technologies

To position cyclotides within the broader landscape of sustainable crop protection, the review compares them across several dimensions with other leading biopesticide technologies:

• Versus RNA interference (RNAi): RNAi relies on sequence-specific gene silencing, but faces challenges from double-stranded RNA (dsRNA) instability and the risk that pests may develop resistance through altered dsRNA uptake or processing pathways. Cyclotides, by contrast, act primarily through direct, non-receptor-mediated membrane interactions, which may reduce the likelihood of resistance development, and they exhibit markedly greater physicochemical stability in the environment.

   

• Versus microbial biopesticides: Bacillus thuringiensis (Bt) Cry proteins act through specific receptor-mediated interactions, and resistance to Bt toxins has been reported in several pests; fungal- and viral-based microbial biopesticides are also often limited by susceptibility to UV radiation. Cyclotides do not depend on specific receptor binding, are regarded as more stable under such conditions, and are considered relatively safe for beneficial insects such as bees.

   

• Versus conventional plant extract-based biopesticides (e.g., neem/azadirachtin): Conventional botanical extracts are typically complex mixtures of secondary metabolites with notable batch-to-batch compositional variability. Cyclotide-rich extracts, while still botanical products, contain a more chemically coherent class of bioactive peptides with unusually high intrinsic stability, making standardisation comparatively more tractable.

   

• Versus animal-derived venom peptides (e.g., the spider-venom-derived peptide in SPEAR): Animal-derived peptides such as those in the commercial product SPEAR primarily target the insect nervous system (e.g., the nicotinic acetylcholine receptor) and, for their labelled lepidopteran applications, are used in combination with Bt toxins. Cyclotides, by contrast, are endogenous plant defence peptides that act primarily through membrane interactions and are naturally deployed against herbivores and pathogens.

4. Evolutionary Origins, Tissue-Specific Deployment, and Immune Regulation

Cyclotide biosynthesis shows strong lineage specificity across the plant kingdom, having been documented in six plant families: Violaceae, Rubiaceae, Cucurbitaceae, Fabaceae, Solanaceae, and Loganiaceae. Key findings include:

• Gene evolution: In Clitoria ternatea (Fabaceae), cyclotide genes arose through expansion and diversification of the albumin-1 gene family, coupled with the functional co-option of asparaginyl endopeptidases (AEPs) — evolving from predominantly proteolytic (hydrolytic) enzymes into ligases capable of efficient backbone cyclisation.

   

• Spatially resolved, organ-specific defence: Plants deploy distinct cyclotide "cocktails" depending on the biotic pressures faced by different organs. For example, in C. ternatea, soil-contacting tissues are enriched in nematode-active cyclotides, while aerial tissues produce variants more active against insect-type membranes.

   

• Integration with inducible immunity: Biotic stress — such as fungal elicitors or spider mite infestation — can upregulate the expression of specific cyclotides, indicating that cyclotides serve not only as part of the plant's constitutive (basal) defence system but are also, in some cases, integrated into pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) signalling networks.

5. Future Challenges and Outlook for Agricultural Application

Despite their considerable commercial and ecological potential as sustainable biopesticides, several bottlenecks must still be addressed before cyclotides can be deployed at scale in agriculture:

2,000+ cyclotides identified to date 36 + 5 cyclotides and acyclotides experimentally validated for pesticidal activity Nanotechnology — an emerging direction for targeted delivery and controlled release.

1. Production costs and scalability bottlenecks. Full chemical synthesis is costly, owing to the need to form multiple disulfide bonds and cyclise the backbone; yields from heterologous expression systems (in plant hosts or microbial fermentation) still require further optimisation. While transgenic plants represent a potentially feasible production route, their development remains constrained by regulatory requirements and concerns over transgene escape.

    

2. Convergence of delivery systems and nanotechnology. Drawing on nanotechnology-enabled antimicrobial peptide (NanoAMP) research in the pharmaceutical field, future work may explore delivery platforms such as mesoporous silica nanoparticles (MSNs) to achieve efficient loading, controlled release, and improved persistence of cyclotides on plant surfaces — though this remains a largely unexplored, speculative direction for cyclotides specifically.

    

3. Refinement of mechanisms and safety validation. Further work is needed to clarify how differences in membrane lipid composition among different pests and pathogens drive the selectivity of specific cyclotides, and comprehensive ecotoxicological evaluation will be required to ensure their safety within integrated pest management (IPM) systems.