“Plant-Derived Peptides: From Identification to Agronomic Applications”

Today, we share a forward-looking perspective article led by the research team of Yi Cai from Sichuan Agricultural University, published in the authoritative plant science journal Molecular Plant. This article systematically elaborates on the immense potential of phytopeptides as next-generation biopesticides and biostimulants. Innovatively proposing a comprehensive innovation system encompassing "plant peptide identification, molecular design, bio-manufacturing, ecological assessment, synergistic innovation of pesticides and seeds, and field application," the paper integrates cutting-edge technologies such as artificial intelligence, nanotechnology, and synthetic biology. It provides a scientifically grounded and feasible systematic solution to address industrial bottlenecks, including the high production costs and poor field stability associated with peptide scale-up.

Research Background 

Global food security is currently confronted with the dual challenges of an ecological crisis triggered by the excessive use of chemical pesticides and the escalating resistance of pathogens. According to statistics from the United Nations Food and Agriculture Organization, plant diseases cause global crop losses of 20% to 40% annually. Meanwhile, the residual contamination and ecological toxicity of traditional chemical pesticides pose serious threats to human health and biodiversity. In this context, phytopeptides, as naturally sourced bioactive molecules with multiple functions—including growth regulation, stress resistance induction, and immune activation—have emerged as disruptive candidates to replace chemical pesticides and fertilizers. By modulating endogenous signaling pathways in plants, phytopeptides demonstrate significant potential in defending against pathogen infection, mitigating abiotic stresses (such as drought and salinity), and optimizing resource allocation. They are regarded as a core breakthrough for next-generation green agricultural technologies. However, their commercialization is hindered by technical bottlenecks such as low efficiency in peptide diversity discovery, high costs of chemical synthesis, reliance on native strains for industrial production, and the lack of precise matching systems for field applications. This article systematically reviews the full-chain technological advancements in phytopeptides from discovery to field application, proposes interdisciplinary solutions, and provides theoretical support and practical pathways for sustainable agricultural development.

Core Technological Breakthroughs and Frontier Advances

1. Multi-Omics Driven Revolution in Peptide Identification Paradigms  

    Traditional peptide discovery methods based on bioassays or genetic screening are inefficient. Emerging technologies significantly enhance efficiency through multi-omics integration and AI empowerment. Researchers combine transcriptomic (RNA-seq), proteomic (MS), and translatome (Ribo-seq) data to break through the identification barriers of peptides encoded by small open reading frames (sORFs) in non-coding regions. For example, a whole-genome scan of maize, by integrating multi-omics data, discovered 1,993 novel non-canonical peptides, 23% of which originate from intronic or UTR regions. Representative achievements include ZmSCREAM1, which regulates stomatal development, and ZmCEP1, involved in phosphorus signaling. AI-driven deep learning models (e.g., AlphaFold2 combined with convolutional neural networks) achieve high-accuracy prediction of mature peptide sequences (accuracy >85%) by training on protease cleavage site features (e.g., Subtilisin-like serine proteases' preference for the RKLL motif). Furthermore, single-cell spatial metabolomics technology has revealed the spatiotemporal distribution patterns of peptides in bundle sheath cells, discovering that PSK signals exhibit a gradient diffusion phenomenon during xylem vessel formation, with the concentration gradient positively correlating with the vessel cell elongation rate (R²=0.87).

2. Function-Oriented Molecular Design and Engineering Optimization  

The functional diversity of plant-derived peptides stems from receptor-ligand co-evolution. Modifying conserved sites in CLE peptides (e.g., Ser11→Ala) through site-saturated mutagenesis can confer Type A functional characteristics to Type B peptides, enabling dual signal output. For instance, the OsCLE45 mutant simultaneously activates root meristem maintenance and lateral root development programs. Chimeric peptide design (e.g., the RGF1-CLE40 fusion peptide) integrates antibacterial and growth-promoting modules, synchronously enhancing disease resistance and root system development in Arabidopsis thaliana, with a synergistic effect 3.2 times higher than that of individual peptides. Innovations in nano-delivery systems significantly improve peptide stability and targeting: pH-responsive liposomes (PEG-PEI nanoparticles) extend the foliar retention time of the antibacterial peptide PIP3 to 72 hours, while the endocytosis pathway mediated by cell-penetrating peptides (CPPs) triples the root absorption efficiency of rice OsPEP1.

3. Industrialization Breakthrough Paths in Biomanufacturing​

Large-scale production of plant-derived peptides faces challenges in chassis cell adaptation and post-translational modifications. Prokaryotic systems (e.g., BL21(DE3)ΔaprEΔvpr) achieve high-yield expression (1.2 g/L) of wheat insect-resistant peptide WheatPep1 by knocking out endogenous protease genes. Plant chassis (e.g., the Nicotiana benthamianatransient expression system) avoid endotoxin contamination, successfully synthesizing the chili disease-resistant peptide Capsaicin (30 mg/g fresh weight). The yeast chassis (Pichia pastoris) resolves the hydroxyproline modification issue in soybean PSK peptide by introducing mammalian prolyl 4-hydroxylase, enhancing biological activity by 40%. Cryo-electron microscopy reveals the dynamic conformational changes of the FERONIA-RALF-RALB ternary complex, providing a structural basis for receptor-ligand co-evolution engineering.

4. Ecological Safety and Microecological Regulation Mechanisms​

The low toxicity and environmental compatibility of plant-derived peptides are core advantages. The LC₅₀of the citrus canker peptide APP3-14 for adult ladybugs is >1000μg/mL, and its mechanism involves selective inhibition of the pathogen flagellar assembly protein (FliC). Metabolomics studies show that PIP3 treatment in wheat increases the abundance of rhizosphere Streptomycesby 2.3-fold, forming a disease-suppressive soil microenvironment lasting for four generations. This effect is closely associated with lipid mediator PDIM-mediated microbial interactions. Synthetic biology strategies (e.g., CRISPRi regulation of root exudates) can directionally shape beneficial microbial communities (e.g., Pseudomonas fluorescens). Field trials demonstrate a 41% reduction in wheat rust incidence in the second season.

5. Collaborative Germplasm Innovation Paradigm for Crops​

Pan-genome analysis and gene-editing technologies facilitate the precise adaptation of plant-derived peptides. The tomato SlPEPR2 receptor exhibits five allelic variants, with SlPEPR2-VAR3 showing a threefold increase in sensitivity to RALF23 compared to the wild type. GWAS mapping identifies the rice OsPP2C15 negative regulatory locus, explaining differences in PSK signal response between indicaand japonicasubspecies (phenotypic variance contribution rate: 18.7%). A CRISPR-Cas12a multi-gene editing system simultaneously knocks out three negative regulators (AtPP2C42/56/78), enhancing the immune response intensity of Arabidopsisto FLG22 by fivefold. Phosphoproteomics reveals that the phosphorylation state of the Thr24 site in OsPIP1 determines its drought stress signal output direction (Ser334 phosphorylation promotes growth, while Ser360 phosphorylation activates defense). This mechanism achieves signal bifurcation via competitive binding to 14-3-3 proteins.

6. Intelligent Field Management Application System​

IoT and AI technologies drive the precise application of plant-derived peptides. Sensor networks monitor leaf water potential (Ψleaf) and stomatal conductance (Gs) in real time, constructing a dynamic application model for PIP3 (threshold: irrigation + peptide spraying triggered when Ψleaf < -0.8 MPa). Field trials show a 28% improvement in water use efficiency. Drones equipped with multispectral cameras identify early symptoms of viral diseases (NDVI decrease >15%), enabling localized precise spraying of antiviral peptides (reducing application volume by 60%). In test areas, the incidence of Tomato yellow leaf curl virus (TYLCV) decreases by 53%. A "peptide-pesticide cocktail" strategy combines the bactericidal peptide Pep1 with a low dose of pyraclostrobin (125 g/ha), achieving 92% control efficacy against potato late blight and reducing the antibiotic resistance risk index (ARI) by 47% compared to chemical control alone. A full-growth-period management regimen—applying growth peptide GRF6 at the seedling stage, switching to disease-resistant peptide WAK1 at the booting stage, and applying stress-resistant peptide COR47 at the grain-filling stage—increases the 1000-grain weight of wheat by 12% and protein content by 1.8%.

Technological Bottlenecks and Future Directions​

Current research still faces three major challenges:

The functional annotation rate for sORF-encoded peptides is less than 23%, necessitating the development of single-cell-resolution spatiotemporal transcriptomics technologies (e.g., seqFISH+ combined with CRISPR activation systems).

Heterologous expression efficiency for complex post-translational modifications (e.g., redox sensitivity of RGD motifs) is low, requiring exploration of plant-derived biodegradable materials (e.g., cellulose derivatives).

Potential microbial resistance from long-term application requires the establishment of rotational application schedules (interval ≥14 days).

Future research will focus on three directions:

Basic Science: Construct a globally shared plant peptide database (PlantPepDB) and develop association analysis tools based on graph neural networks.

Technological Innovation: Design light/magnetic dual-responsive nanocarriers and promote the commercialization of "plug-and-play" industrial fermentation platforms.

Industrial Translation: Leverage policy-driven collaborative innovation (e.g., the EU EFSA "Ecological Benefit Credit System") to accelerate the entry of the first certified products into fast-track approval channels such as the U.S. EPA.

Summary and Outlook

The agricultural application of plant-derived peptides has entered a critical stage of technological breakthroughs. The core challenge lies in overcoming bottlenecks across the entire chain of "discovery-design-manufacturing-application." Through multidisciplinary collaborative research—integrating AI-driven multi-scale modeling, chassis reconstruction technologies from synthetic biology, and intelligent delivery systems from nanomedicine—plant-derived peptides are poised to become a disruptive agricultural technology that balances production efficiency, ecological safety, and economic benefits. With the first plant-derived peptide-based biopesticide (such as Vestaron's Spear-T) entering the commercialization stage globally, this field is expected to lead the Third Green Revolution in Agriculture, providing dual guarantees for food security and ecological conservation. Moving forward, it is essential to further promote interdisciplinary research, policy support, and industrial collaboration to achieve a quantum leap in development from laboratory innovation to field practice for plant-derived peptides.

Original Article：

Yu X, Liu J, Wang W, et al. Plant-derived peptides: from identification to agronomic applications[J]. Molecular Plant, 2025.

https://www.sciencedirect.com/science/article/pii/S1674205225003910