Use of Oil, Aqueous Extracts, and Formulations of Azadirachta indica A. Jussieu against Spodoptera frugiperda: A Systematic Review (2015–2026)

Use of Oil, Aqueous Extracts, and Formulations of Azadirachta indica A. 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Jussieu against Spodoptera frugiperda : A Systematic Review (2015–2026) Humberto Giraldo-Vanegas, Gabriel Giraldo-Herrera This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9361769/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The fall armyworm, Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae), is one of the most economically damaging cereal pests globally, with yield losses exceeding 30%. The neem tree, Azadirachta indica A. Jussieu (Meliaceae), contains over 200 bioactive secondary metabolites, with azadirachtin A (C₃₅H₄₄O₁₆) as the most potent insecticidal compound. This review systematizes scientific evidence published between 2015 and 2026 on the use of oil, aqueous extracts, and formulations of A. indica against S. frugiperda under laboratory and field conditions, analyzing formulation efficacy, multi-target mechanisms of action, and the influence of high-altitude climatic conditions on biopesticide performance. Formulated neem oil at 500–1,500 µL/L achieves larval mortality exceeding 70% in early instars (L1–L3), with LC₅₀ = 580–703 µL/L and LT₅₀ = 21–67 h. Metabolite modes of action include ecdysteroid antagonism, gustatory inhibition, intestinal cytotoxicity, immunosuppression, and enzymatic inhibition of detoxification systems (Tables 1 and 3), constituting a multi-target strategy that minimizes resistance development risk in S. frugiperda . Emerging nanoformulations (microencapsulation, chitosan-azadirachtin nanoparticles) show LC₅₀ values up to 2.5-fold lower and extended environmental half-lives of 7–21 days compared with conventional emulsifiable concentrates, constituting a priority area for future research and commercial development. Agronomy Agroecology Spodoptera frugiperda Azadirachta indica botanical insecticides biopesticides phytochemistry integrated pest management Andean agroecosystems nanoformulations 1. Introduction 1.1. Spodoptera frugiperda (J. E. Smith): Biology, Global Expansion, and Economic Impact Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae) is recognized as one of the most economically important agricultural pests on a global scale (Montezano et al., 2018 ; Tay et al., 2023 ). This polyphagous lepidopteran, native to tropical and subtropical regions of the Americas, has the capacity to attack more than 400 plant species, with a marked preference for agronomically important grasses such as maize [ Zea mays L.], sorghum [ Sorghum bicolor (L.) Moench], rice [ Oryza sativa L.], and cotton ( Gossypium hirsutum L.) (Casmuz et al., 2010 ; Early et al., 2018 ). Yield losses in maize attributable to S. frugiperda are estimated at 18–30% of global production, representing billions of dollars annually (Montezano et al., 2018 ; Machekano et al., 2024 ). Since its first detection outside the Americas in West Africa in 2016, S. frugiperda dispersed to 44 African countries within three years, reaching the Asian continent between 2018 and 2019 — India, China, Thailand, Myanmar, Bangladesh, and Sri Lanka — and Australia in 2020 (Goergen et al., 2016 ; Ganiger et al., 2018 ; Sun et al., 2021 ). In China, associated economic losses are estimated at USD 2.46–6.18 billion annually (Liu et al., 2025 ). Its biological characteristics — high fecundity (1,000–1,500 eggs per female), short life cycle (30–40 days), and flight capacity of up to 100 km per night — favor its persistence as a transboundary pest (Tay et al., 2023 ). Control of S. frugiperda has historically depended on intensive use of synthetic organophosphate, pyrethroid, and carbamate insecticides. However, high-level resistance (> 100×) has been documented in populations from Brazil, Puerto Rico, Mexico, and several Asian countries (Carvalho et al., 2013 ; Gutiérrez-Moreno et al., 2019 ; Silva-Brandão et al., 2024 ). The use of Cry proteins from Bacillus thuringiensis Berliner in transgenic cultivars has also generated field-level resistance (Boaventura et al., 2020 ; Nascimento et al., 2021 ). Against this backdrop, the development of sustainable biorational alternatives within Integrated Pest Management (IPM) has become a priority in applied entomological research (Isman, 2020 ; Pavela & Benelli, 2023 ). 1.2. Azadirachta indica A. Jussieu: Secondary Metabolites and Insecticidal Activity The neem tree, Azadirachta indica A. Jussieu (Meliaceae), contains more than 200 bioactive compounds distributed in four major groups (Table 1 ): (i) tetranortriterpene limonoids, of which the most active is azadirachtin A (C₃₅H₄₄O₁₆, MW = 720.7 g/mol, 16 stereocenters); (ii) secondary limonoids such as salannin (C₃₄H₄₄O₉), nimbin (C₃₀H₃₆O₉), gedunin (C₂₈H₃₄O₇), and azadiradione (C₂₈H₃₄O₄); (iii) flavonoids and polyphenols (catechin, epicatechin, quercetin, kaempferol) and diterpenoids (margolones); and (iv) the phytosterol β-sitosterol (C₂₉H₅₀O) and the fatty acids oleic and linoleic acids, which are the major components of seed oil (Schmutterer, 1990 ; Mordue & Nisbet, 2000 ; Koul, 2004 ). Azadirachtin A exerts a multimodal insecticidal action including: (i) ecdysteroid and juvenile hormone antagonism through interference with the nuclear receptors EcR/USP and Met/FISC; (ii) feeding inhibition by blockade of gustatory chemoreceptors; (iii) intestinal cytotoxicity through apoptosis of epithelial cells; and (iv) immunotoxicity with suppression of phenoloxidase (PO) and cellular encapsulation (Mordue & Blackwell, 1993 ; Mordue et al., 2010 ; Kumar et al., 2024 ). This multi-target mechanism significantly reduces the risk of resistance development in S. frugiperda compared with single-site synthetic insecticides (Isman, 2015 ; Sparks & Nauen, 2015 ). 1.3. Review Objectives The primary objective of this review is to critically and systematically analyze the scientific evidence published between 2015 and 2026 on the use of oil, aqueous extracts, and formulations of A. indica against S. frugiperda (J. E. Smith) under laboratory and field conditions (Table 2 ), integrating knowledge on the multi-target modes of action of its metabolites (Tables 1 and 3 ) to inform recommendations for IPM programs. As a secondary objective, the influence of high-altitude climatic conditions on formulation efficacy and the pest's ecophysiology is examined. 2. Bibliographic Search Methodology The bibliographic search was conducted in the Scopus, Web of Science, PubMed, Google Scholar, SciELO, and AGRIS databases, covering publications from January 2015 to March 2026. Search terms employed, combined using Boolean operators (AND, OR, NOT), included: " Spodoptera frugiperda ", "neem", " Azadirachta indica ", "azadirachtin", "neem oil", "NSKE", "botanical insecticide", "biopesticide", "fall armyworm control", and their Spanish equivalents. Original research articles, systematic reviews, and indexed postgraduate theses published between 2015 and 2026 were included. Studies without access to full text, without quantitative efficacy results, or involving species other than S. frugiperda or formulations other than A. indica were excluded. Of 187 references initially identified, 68 met inclusion criteria. The 28 most representative studies and reviews are synthesized in Table 2 . 3. Results and Discussion 3.1. Studies on the Use of Azadirachta indica against Spodoptera frugiperda Table 2 synthesizes the studies and reviews identified that evaluated the use of A. indica formulations against S. frugiperda between 1990 and 2026. Of the total, ten correspond to laboratory trials, six to field or mixed (laboratory/field) trials, and seven to bibliographic reviews. Geographically, studies are concentrated in Latin America (Ecuador, Mexico, Nicaragua, Colombia), Asia (India, China), Africa (Zimbabwe, Botswana, South Africa), and Europe (Italy, Czech Republic). Formulations comprise emulsifiable concentrate (EC) oil, neem seed kernel extract (NSKE), technically purified azadirachtin, and emerging nanotechnology-based formulations. Table 2 Studies on the use of Azadirachta indica A. Jussieu formulations against Spodoptera frugiperda (J. E. Smith) under laboratory and field conditions (1990–2026). Author(s) Year Formulation/Product Type Setting Country/Region Main finding Schmutterer 1990 Oil, botanical extracts Review Review Germany Foundational characterization of neem chemistry and insecticidal activity Mordue & Blackwell 1993 Purified azadirachtin Azadirachtin Laboratory United Kingdom Elucidated multi-target mode of action of azadirachtin García et al. 1999 Neem botanical extract Aqueous extract Field Colombia Field efficacy against S. frugiperda in maize Mordue & Nisbet 2000 Purified azadirachtin Azadirachtin Laboratory United Kingdom Comprehensive review of azadirachtin action in insects Nathan et al. 2005 Neem limonoids Aqueous extract Laboratory India Limonoid activity on vector mosquito Anopheles stephensi Charleston et al. 2006 A. indica + M. azedarach extract Aqueous extract Field South Africa Impact on Plutella xylostella populations and natural enemies Isman 2006 Botanical insecticides Review Review Canada Global overview of botanical insecticides in modern agriculture Gutiérrez et al. 2010 Formulated neem oil (EC) Formulated oil Lab/Field Mexico LC₅₀ = 720–950 µL/L for L3–L5 at 22°C Senthil-Nathan 2013 Meliaceae extracts Aqueous extract Lab/Review India Biochemical effects of neem limonoids on Lepidoptera Isman 2015 Botanical insecticides Review Review Canada Renaissance of botanical insecticides and regulatory outlook Campos et al. 2016 Neem oil, NSKE Oil/NSKE Review Brazil Neem oil in crop protection: current status and future Isman 2020 Botanical insecticides Review Review Canada 21st-century botanical insecticides: innovation and going green Almeida 2021 Neem oil + vegetable oil Formulated oil Laboratory Ecuador Larvicidal efficacy in maize against S. frugiperda Gámez 2021 Botanical extract (neem, Eucalyptus spp., Capsicum annuum L.) Aqueous extract Laboratory Nicaragua Mortality 58–78% (NSKE 5%) and 80–88% (NSKE 10%) in L2–L4 López et al. 2022 EC oil + NSKE 3–10% Oil/NSKE Lab+Field Ecuador LC₅₀ = 650–840 µL/L for L2–L4; antifeedant effect 65–75% Pavela & Benelli 2023 Essential oils and neem Review Review Czech Rep./Italy Challenges of botanical insecticides as ecofriendly biopesticides Cantrell et al. 2024 Natural products as pesticides (incl. neem) Review Review USA Opportunities and constraints for natural product pesticides Kumar et al. 2024 Oil, extracts, limonoids Oil/extract Review India Neem potential for animal and human health safeguarding Machekano et al. 2024 Commercial neem formulations Formulated oil Field/Review Africa (Zimbabwe, Botswana) FAW biology, ecology, genetic diversity and management in Africa Bezerra et al. 2025 Microencapsulated/photoresistant A. indica extract Emerging form. Lab/Semi-field Brazil Extended half-life and improved efficacy against S. frugiperda under semi-field conditions Harrison et al. 2019 Agroecological options incl. neem Review Field/Review Sub-Saharan Africa FAW management options; neem as low-cost smallholder-friendly solution Pavela et al. 2025 Botanical insecticides Review Review Czech Rep./Italy Criteria for biopesticide commercialization in the 21st century Wu et al. 2025 O-carboxymethyl chitosan-azadirachtin nanoformulation Emerging form. Laboratory China Nanoformulation improves azadirachtin stability; enhanced antifeedant against S. frugiperda Cañas-Meaury et al. 2025 NeemAZAL® 1.2% EC Formulated oil Laboratory Colombia (Pamplona) Instar-specific larvicidal efficacy at 2,586 m a.s.l. Reatiga-Pulido et al. 2025 NeemAZAL® 1.2% EC Formulated oil Laboratory Colombia (Pamplona) Instar toxicity analysis under high-altitude laboratory conditions Giraldo-Vanegas et al. 2026a NeemAZAL® 1.2% EC — dose-response and survival analysis Formulated oil Laboratory Colombia (Pamplona) LC₅₀ = 579.67–921.36 µL/L across L1–L6; R² = 0.94–0.95 Giraldo-Vanegas et al. 2026b NeemAZAL® 1.2% EC — ontogenetic thresholds and LT dynamics Formulated oil Laboratory Colombia (Pamplona) LT₅₀ = 52.39 h (L1) to 196.69 h (L5); 271.3% ontogenetic gradient Note. EC = emulsifiable concentrate; NSKE = Neem Seed Kernel Extract; Lab. = laboratory; Rev. = bibliographic review; a.s.l. = above sea level. Source: compiled by the authors. The analysis of Table 2 reveals a sustained increase in publications from 2020 onward, coinciding with the global expansion of S. frugiperda to Asia and Oceania. The works of Giraldo-Vanegas et al. ( 2026a , b ), Cañas-Meaury et al. ( 2025 ), and Reatiga-Pulido et al. ( 2025 ), conducted under high-altitude conditions in Pamplona, Norte de Santander, Colombia (2,586 m a.s.l., 17 ± 1°C), are the only studies that simultaneously evaluate all six larval instars of S. frugiperda with formulated azadirachtin, constituting the most ontogenetically comprehensive works available for the Colombian Andean region. 3.2. Phytochemical Characterization of the Defensive Complex of Azadirachta indica The efficacy of neem formulations against S. frugiperda does not reside in a single active ingredient, but in the synergy of diverse chemical families (Koul, 2004 ; Schmutterer, 1990 ). More than 20 target metabolites form the core of the biological activity, classified into four main groups: limonoids and triterpenoids, phytosterols and amide alkaloids, oxygenated diterpenoids, and the flavonoid-polyphenol complex (Table 1 ). Table 1 Principal secondary metabolites of Azadirachta indica A. Jussieu with documented biological activity against insect pests. Metabolite Mol. formula MW (g/mol) CAS No. Plant part Primary biological activity Azadirachtin A C₃₅H₄₄O₁₆ 720.7 11141-17-6 Seed Ecdysteroid antagonism, antifeedant (60–90%), intestinal cytotoxicity, immunosuppression, CYP/GST inhibition Azadirachtin B C₃₅H₄₄O₁₆ 720.7 11141-17-6 Seed Isomer B; lower biological activity than A Salannin C₃₄H₄₄O₉ 596.7 992-20-1 Seed Potent antifeedant; immediate action on gustatory chemoreceptors Nimbin C₃₀H₃₆O₉ 556.6 13030-24-5 Seed, bark Immunosuppressant; antifungal; synergist with azadirachtin Gedunin C₂₈H₃₄O₇ 482.6 2753-30-2 Seed Hsp90 inhibitor; amplifies EcR disruption; antimalarial Azadiradione C₂₈H₃₄O₄ 450.6 18472-36-1 Seed, leaf Contact insecticide; cuticle disruption; antibacterial β-Sitosterol C₂₉H₅₀O 414.7 83-46-5 Seed oil Competitive antagonist EcR/USP receptor; analog of 20-HE Quercetin C₁₅H₁₀O₇ 302.2 117-39-5 Leaf, bark CYP P450 and GST inhibitor; pro-oxidant; antibacterial Kaempferol C₁₅H₁₀O₆ 286.2 520-18-3 Leaf Co-inhibitor CYP P450; antifungal; synergist with azadirachtin Oleic acid (18:1 Δ⁹-cis) C₁₈H₃₄O₂ 282.5 112-80-1 Seed oil Primary lipid vehicle (50–60%); enhances transdermal penetration of azadirachtin Linoleic acid (18:2 Δ⁹,¹²) C₁₈H₃₂O₂ 280.4 60-33-3 Seed oil Co-vehicle (15–20%); generates LOOHs under UV → secondary oxidative stress Salannol C₃₂H₄₄O₈ 564.7 78012-51-8 Seed Complementary limonoid; synergistic antifeedant Nimbinene C₂₈H₃₄O₇ 482.6 78916-54-8 Seed High lipophilicity; synergistic activity with azadirachtin Nimbolin A C₃₉H₄₆O₈ 650.8 24480-41-9 Seed Antagonistic interactions with digestive enzymes Azadiramide A Amide alkaloid — No universal CAS Leaf, seed Neurotoxic properties; characterized by NMR Margolone C₁₉H₂₄O₃ 300.4 120092-48-0 Seed Tricyclic diterpenoid; intestinal epithelium cytotoxicity Margolonone C₁₉H₂₂O₄ 314.4 120092-49-1 Seed Oxidized derivative; lipid homeostasis disruption (+)-Catechin C₁₅H₁₄O₆ 290.3 154-23-4 Leaf CYP P450 and GST inhibition (trans configuration); synergistic oxidative stress (−)-Epicatechin C₁₅H₁₄O₆ 290.3 490-46-0 Leaf Isomer (cis); co-inhibitor of detoxification systems Note. MW = molecular weight; CAS = Chemical Abstracts Service; 20-HE = 20-hydroxyecdysone; EcR/USP = ecdysone receptor/ultraspiracle protein; LOOHs = lipid hydroperoxides. Source: compiled by the authors after Schmutterer ( 1990 ), Mordue & Nisbet ( 2000 ), Koul ( 2004 ), and Nicoletti et al. ( 2023 ). 3.2.1. Limonoids and Triterpenoids Tetranortriterpenoids constitute the most potent biological markers of neem, characterized by a highly oxygenated fused ring system (Kraus, 1995 ; Schmutterer, 1990 ). Azadirachtin A (C₃₅H₄₄O₁₆, CAS 11141-17-6) presents a pentacyclic skeleton (rings A–B–C–D–E) with 16 stereocenters. Salannin (C₃₄H₄₄O₉), a seco-limonoid with an open B ring, exhibits antifeedant potency superior to azadirachtin A at equivalent concentrations. Salannol (C₃₂H₄₄O₈), nimbinene (C₂₈H₃₄O₇), and nimbolin A (C₃₉H₄₆O₈) complement the limonoid profile with antagonistic interactions on insect digestive enzymes and chemoreceptors. 3.2.2. Phytosterols, Amide Alkaloids, and Diterpenoids β-Sitosterol (C₂₉H₅₀O, CAS 83-46-5), present at 0.8–1.2% of seed oil, acts as a competitive antagonist of 20-hydroxyecdysone (20-HE) for the nuclear receptor EcR/USP (Behmer & Nes, 2003 ). Azadiramide A, an amide alkaloid characterized by NMR in leaves and seeds, exhibits neurotoxic properties (Siddiqui et al., 2004 ). Margolones (C₁₉H₂₄O₃ and C₁₉H₂₂O₄, CAS 120092-48-0 and 120092-49-1) are tricyclic diterpenoids associated with cytotoxicity in the intestinal epithelium and disruption of larval lipid homeostasis (Koul, 2004 ). 3.2.3. Flavonoid and Polyphenolic Complex Flavonoids are fundamental for the inhibition of detoxification systems and the generation of oxidative stress in polyphagous insects (Salminen & Karonen, 2011 ; Simmonds, 2001 ). Quercetin (C₁₅H₁₀O₇, CAS 117-39-5) and kaempferol (C₁₅H₁₀O₆, CAS 520-18-3), present in leaves of A. indica , competitively inhibit CYP6 and CYP9 monooxygenases and glutathione-S-transferases (GSTs). (+)-Catechin (C₁₅H₁₄O₆, CAS 154-23-4) and (−)-epicatechin (C₁₅H₁₄O₆, CAS 490-46-0) differ in the relative configuration of C2–C3 carbons (trans and cis, respectively), which determines variations in their affinity for detoxification enzymes. Both flavanols synergize with the limonoids of crude oil, incapacitating the insect from neutralizing the toxic complex (Riaz et al., 2014 ). 3.3. Formulation Efficacy under Laboratory Conditions 3.3.1. Acute Toxicity Parameters: LC₅₀ and LT₅₀ Neem oil formulated as an emulsifiable concentrate (EC) with azadirachtin A content between 0.5% and 3% has demonstrated significant insecticidal activity against the different larval instars of S. frugiperda (Table 2 ). López et al. ( 2022 ) determined, through Probit analysis, LC₅₀ values of 650–840 µL/L for L2–L4 larvae in Ecuador (25°C; R² = 0.93–0.95). Gutiérrez et al. (2010) reported LC₅₀ values of 720–950 µL/L for L3–L5 in Mexico (22°C), and Gámez ( 2021 ) obtained 590–780 µL/L for L1–L3 in Nicaragua (27°C). Giraldo-Vanegas et al. ( 2026a , b ) determined the toxicological parameters of NeemAZAL® 1.2% EC for all six larval instars of S. frugiperda under Colombian high-altitude conditions, obtaining Probit models with R² = 0.94–0.95. LC₅₀ values ranged from 579.67 µL/L (L1) to 921.36 µL/L (L6), with a 58.9% increase in the required concentration from first to sixth instar, adjustable to the model: LC₅₀ = 472.8 + 74.3 × instar (R² = 0.986; p < 0.001). The LT₅₀ was 52.39 h for L1, increasing to 196.69 h in L5 (271.3% increment). This ontogenetic susceptibility gradient is grounded in: (i) progressive cuticle thickening (~ 2 µm in L1 to ~ 15 µm in L6); (ii) a 4.2–6.8-fold increase in CYP6/CYP9 expression between L1 and L5 (Huang et al., 2023 ; Wang et al., 2023 ); (iii) toxicokinetic dilution due to body mass increase (~ 89-fold between L1 and L6); and (iv) a robust cellular immune response in advanced instars (Lavine & Strand, 2002 ). 3.3.2. Sublethal Effects on Biological Parameters Beyond direct mortality, A. indica formulations exert significant sublethal effects. At sublethal concentrations (LC₂₅–LC₁₀), reductions in foliar consumption of 55–72% and weight gain of 40–65% are documented in L2–L4 larvae (Schmutterer, 1990 ; López et al., 2022 ). Exposure of L5–L6 larvae to 500–800 µL/L of formulated azadirachtin results in frequencies of malformed pupae of 20–45% and adults with deformed wings of 15–30%. Almeida ( 2021 ) reported a reduction in fecundity of 20–35% and egg viability of 15–40% in adults emerging from treated larvae, evidencing transgenerational effects (Isman, 2020 ; Pavela & Benelli, 2023 ). 3.4. Aqueous Extracts and Emerging Formulations Neem seed kernel extract (NSKE) at 5% is one of the most studied formulations due to its low cost and availability (Campos et al., 2016 ; Isman, 2020 ). Gámez ( 2021 ) reported mortalities of 58–78% at 72 h with NSKE at 5% in L2–L4 larvae. López et al. ( 2022 ) demonstrated that NSKE at 10% achieved mortalities of 80–88% at 96 h, statistically equivalent to those of formulated oil at 1.0 mL/L, with antifeedant effects of 65–75% even at 3%. Extracts of A. indica leaves, with contributions of nimbin (C₃₀H₃₆O₉) and gedunin (C₂₈H₃₄O₇), show mortalities of 45–65% in L1–L2 at concentrations of 10% in water (Machekano et al., 2024 ). Emerging formulations — nanoemulsions, microencapsulated azadirachtin, and chitosan-azadirachtin nanocomposites — present LC₅₀ values up to 2.5-fold lower and extended environmental half-lives of 7–21 days compared with conventional EC formulations (Bezerra et al., 2025 ; Wu et al., 2025 ). Wu et al. ( 2025 ) demonstrated that O-carboxymethyl chitosan-based azadirachtin nanoformulations substantially improve the anti-degradation properties of azadirachtin and significantly enhance antifeedant activity against S. frugiperda , representing a major advance in the field of neem-based biopesticide technology. Cantrell et al. ( 2024 ) place these developments within the broader framework of natural product-based pesticide innovation, underscoring the importance of precision delivery systems in overcoming the photolability limitations of azadirachtin. 3.5. Field Efficacy Field studies report efficacies of formulated neem oil (1.0–2.0 mL/L) of 40–85% reduction in foliage damage in Z. mays crops (Gutiérrez et al., 2010; López et al., 2022 ; Machekano et al., 2024 ). Harrison et al. ( 2019 ), in a review of sub-Saharan African trials, found that applications directed at L1–L2 achieved damage reductions of 65–85%, while late applications on L4–L6 showed efficacies of 30–50%. Photodegradation of azadirachtin A under direct solar radiation reduces its half-life to 1–4 days, requiring applications every 5–7 days to maintain acceptable control levels (Stark & Walter, 1995 ; Barrek et al., 2004 ). In high-altitude Andean agroecosystems, Giraldo-Vanegas et al. ( 2026a , b ) employed applications at 5–7-day intervals, evidencing the technical necessity of UV-protective microemulsions or co-adjuvants. 3.6. Multi-Target Modes of Action The metabolites of A. indica act on S. frugiperda through complementary biochemical mechanisms that affect multiple insect systems simultaneously or sequentially (Table 3 ). This multi-target attack strategy saturates the phenotypic plasticity of the pest, minimizing the selection of resistant biotypes (Isman, 2020 ; Sparks & Nauen, 2015 ). Table 3 Mode of action of principal metabolites of Azadirachta indica A. Jussieu on Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae). Metabolite Mol. formula Target / Site of action Mechanism and main effect Instar References Azadirachtin A C₃₅H₄₄O₁₆ EcR/USP and Met/FISC receptors; gustatory chemoreceptors; intestinal epithelium; hemocytes Ecdysteroid antagonism (molting blockage); antifeedant 60–90% ingesta; intestinal apoptosis; ↓PO; downregulates CYP6/CYP9/GSTs L1–L6 Mordue & Blackwell, 1993 ; Kumar et al., 2024 ; Giraldo-Vanegas et al., 2026a , 2026b Salannin C₃₄H₄₄O₉ Chemoreceptor deterrent neurons (maxillary palps) Immediate antifeedant (minutes); nanomolar EC₅₀; ↓foliar consumption 65–90% in L2–L4; no systemic absorption L2–L4 Mordue & Blackwell, 1993 ; Senthil-Nathan, 2013 ; López et al., 2022 Nimbin C₃₀H₃₆O₉ Hemocytes (PO, antimicrobial peptides); peritrophic membrane Immunosuppression: ↓PO; ↑peritrophic permeability; facilitates secondary penetration of azadirachtin into hemocoel (L3–L5); synergist L3–L5 Schmutterer, 1990 ; Senthil-Nathan, 2013 ; Machekano et al., 2024 Gedunin C₂₈H₃₄O₇ Hsp90 (N-terminal/ATP domain); EcR receptor; fat body Inhibits Hsp90 → ubiquitin-proteasome degradation of EcR complex; amplifies molting disruption in L3–L5 L3–L5 Senthil-Nathan, 2013 ; Kumar et al., 2024 Azadiradione C₂₈H₃₄O₄ Epicuticular membrane (contact); intestinal microbiome Contact insecticide: cuticle disruption (log P ≈ 4.2); broad-spectrum antibacterial on midgut microbiome L1–L6 Schmutterer, 1990 ; Campos et al., 2016 β-Sitosterol C₂₉H₅₀O EcR/USP receptor; midgut lipid membrane domains Competitive antagonism of 20-HE; saturates ecdysteroid signaling; interferes with membrane biosynthesis L1–L6 Schmutterer, 1990 ; Behmer & Nes, 2003 Quercetin C₁₅H₁₀O₇ CYP6/CYP9 (phase I); GSTs (phase II); hemocyte mitochondria; microbiome ↑azadirachtin half-life 15–30%; caspase-3/9 apoptosis at > 100 µM; bacteriostatic on intestinal microbiome L2–L5 Huang et al., 2023 ; Simmonds, 2001 Kaempferol C₁₅H₁₀O₆ CYP P450; intestinal microbiome Co-inhibits CYP P450; antifungal on microbiome; synergist with azadirachtin in L2–L4 L2–L4 Senthil-Nathan, 2013 Oleic acid (Δ⁹-cis) C₁₈H₃₄O₂ Epicuticular surface lipids Primary lipid vehicle (50–60%); Δ⁹-cis geometry improves transcuticular diffusion of azadirachtin L1–L6 Campos et al., 2016 Linoleic acid (Δ⁹,¹²) C₁₈H₃₂O₂ Epicuticular surface; contact membranes Co-vehicle (15–20%); generates LOOHs under UV → secondary oxidative stress on cuticle L1–L6 Campos et al., 2016 Catechin/Epicatechin C₁₅H₁₄O₆ CYP P450; GSTs; peritrophic membrane Inhibition of detoxification phase I and II enzymes; synergistic oxidative stress L2–L5 Riaz et al., 2014 ; Salminen & Karonen, 2011 Margolones C₁₉H₂₄/₂₂O₃/₄ Intestinal epithelium; lipid membrane domains Cytotoxicity in midgut mesenterone; peritrophic membrane destruction; lipid homeostasis disruption L1–L4 Schmutterer, 1990 ; Koul, 2004 Note. EcR/USP = ecdysone receptor/ultraspiracle protein; Met/FISC = juvenile hormone receptor; PO = phenoloxidase; CYP = cytochrome P450; GSTs = glutathione-S-transferases; LOOHs = lipid hydroperoxides; 20-HE = 20-hydroxyecdysone; Hsp90 = 90 kDa chaperone protein. Source: compiled by the authors. 3.6.1. Azadirachtin A: Neuroendocrine Antagonism and Cytotoxicity Azadirachtin A (C₃₅H₄₄O₁₆, MW = 720.7 g/mol) acts through four principal mechanisms on S. frugiperda : (i) neuroendocrine antagonism , competing with 20-HE and juvenile hormone (JH-III) for the nuclear receptors EcR/USP and Met/FISC, blocking early ecdysis genes (E74, Broad-Complex, HR3) and preventing synthesis of new cuticle, generating exuvia retention and mortality during ecdysis (Mordue & Blackwell, 1993 ; Martinez & van Emden, 2001 ); (ii) feeding inhibition , blocking gustatory chemoreceptors of the maxillary palps and suppressing ingestion by 60–90% (Mordue et al., 2010 ); (iii) intestinal cytotoxicity , inducing apoptosis in columnar cells of the intestinal epithelium with cytoplasmic vacuolization, loss of microvilli, and permeabilization of the peritrophic membrane (Zhang et al., 2023 ); (iv) immunosuppression and gene regulation , suppressing phenoloxidase (PO) and negatively regulating CYP6, CYP9, and GSTs (Huang et al., 2023 ; Wang et al., 2023 ). 3.6.2. Salannin, Nimbin, Gedunin, and Azadiradione Salannin (C₃₄H₄₄O₉) specifically activates deterrent chemoreceptor neurons with nanomolar binding constants, generating immediate rejection without systemic absorption (Senthil-Nathan, 2013 ). Nimbin (C₃₀H₃₆O₉) exerts immunosuppressive activity on granular hemocytes and plasmatocytes, inhibiting PO and antimicrobial peptide synthesis, and alters peritrophic membrane permeability, facilitating secondary penetration of azadirachtin A into the hemocoel in L3–L5 larvae (Schmutterer, 1990 ; Machekano et al., 2024 ). Gedunin (C₂₈H₃₄O₇) competitively inhibits Hsp90 of S. frugiperda , causing ubiquitin-proteasome degradation of the EcR complex and amplifying molting disruption in L3–L5 (Kumar et al., 2024 ). Azadiradione (C₂₈H₃₄O₄, log P ≈ 4.2) acts as a contact insecticide on the epicuticular membrane and exhibits antibacterial activity against the intestinal microbiome (Schmutterer, 1990 ; Campos et al., 2016 ). 3.6.3. Flavonoids and Fatty Acids: Enzymatic Synergy and Vehicular Function Quercetin (C₁₅H₁₀O₇) competitively inhibits CYP6 and CYP9 monooxygenases (phase I) and GSTs (phase II), prolonging the systemic half-life of azadirachtin by 15–30% (Huang et al., 2023 ); at concentrations > 100 µM it acts as a pro-oxidant in hemocytes, activating caspase-3/9 apoptotic pathways (Simmonds, 2001 ). Kaempferol (C₁₅H₁₀O₆) co-inhibits CYP P450 and maintains antifungal activity and synergy with azadirachtin in L2–L4 (Senthil-Nathan, 2013 ). Catechin and epicatechin (C₁₅H₁₄O₆, trans and cis configurations, respectively) inhibit phase I and II detoxification enzymes, incapacitating the insect from neutralizing the toxic complex (Riaz et al., 2014 ). Oleic acid (C₁₈H₃₄O₂, 50–60% of the oil), through its Δ⁹-cis geometry, improves the cuticular penetration of azadirachtin by interacting with epicuticular lipids. Linoleic acid (C₁₈H₃₂O₂, 15–20%) acts as a co-vehicle and can generate lipid hydroperoxides (LOOHs) under UV radiation, contributing to cuticular oxidative stress (Campos et al., 2016 ). 3.7. Chronic Impact and Suppression of Reproductive Dynamics The impact of neem formulations on S. frugiperda transcends the lethal control of immature stages. Endocrine disruption significantly reduces juvenile hormone (JH) titers in females, blocking vitellogenin synthesis in the fat body, causing severe ovarian atrophy and subclinical sterility (Medina et al., 2004 ). Transfer of limonoid residues to egg chorion prevents embryogenesis (trans-ovarian ovicidal effect), while in exposed males a drastic reduction in sperm motility is documented (Sáenz-de-Cabezón et al., 2005 ). The high sensitivity of gravid females to polyphenols present on treated leaf surfaces triggers an oviposition deterrence response mediated by tarsal and ovipositor receptors (Viana & Prates, 2003 ). This set of chronic effects strengthens the role of neem as an integral tool in IPM of S. frugiperda . 3.8. Influence of Altitude and High-Altitude Climatic Conditions In Andean agroecosystems such as those of Pamplona, Norte de Santander (2,586 m a.s.l., 17 ± 1°C), climatic variables substantially modify the stability of extracts and the ecophysiology of S. frugiperda . At higher altitude, the reduced atmospheric filtration increases the incidence of ultraviolet radiation, accelerating the photooxidation of photolabile limonoids and reducing their half-life on the foliar canopy (Barrek et al., 2004 ; Isman, 2020 ). The works of Giraldo-Vanegas et al. ( 2026a , b ) under these conditions employed 5–7-day application intervals, evidencing the technical necessity of microemulsions or UV-protective adjuvants. The emerging nanoformulations reported by Wu et al. ( 2025 ) and Bezerra et al. ( 2025 ), which extend azadirachtin half-life to 7–21 days, represent particularly promising solutions for high-altitude Andean conditions. From a thermodynamic standpoint, the high-altitude mountain climate reduces the basal metabolic rate of poikilotherm insects. In S. frugiperda , this prolongs the duration of each larval stadium (García-Roa et al., 1999 ; Núñez-García et al., 2024 ), extending the exposure window to the biopesticide, while also decreasing the foliar consumption rate and ingestion of active principles (Smirle et al., 1996 ). Nevertheless, low temperatures also depress the enzymatic efficiency of GST and oxidases in the insect, shifting the locus of control from acute mortality toward sustained endocrine disruption that collapses molting and sterilizes adult populations. The LT₅₀ values documented by Giraldo-Vanegas et al. ( 2026b ) — up to 196.69 h in L5 at 17°C — reflect this particular temporal dynamics of neem biological activity under Andean conditions. 4. Conclusions The bibliographic review synthesized in Table 2 (28 studies, 1990–2026) and the analysis of the phytochemical profile of A. indica A. Jussieu (Tables 1 and 3 ) allow the following conclusions on the use of its formulations against S. frugiperda (J. E. Smith). Formulations of A. indica — especially EC oil and NSKE — exert significant insecticidal and antifeedant activity on S. frugiperda , with differential susceptibility favoring control of L1–L3 instars (LC₅₀ = 580–703 µL/L; LT₅₀ = 21–67 h) compared with L4–L6 (LC₅₀ = 795–921 µL/L; LT₅₀ = 90–410 h). The critical physiological threshold between L3 and L4 is associated with cuticle thickening, increased CYP6/CYP9 expression, and toxicokinetic dilution documented by Wang et al. ( 2023 ) and Giraldo-Vanegas et al. ( 2026a , b ). This threshold determines the optimal application window for maximum efficacy. The multi-target mechanisms of action of A. indica metabolites — ecdysteroid antagonism, gustatory inhibition, intestinal cytotoxicity, immunosuppression, and enzymatic inhibition of detoxification systems — constitute a strategy that saturates the phenotypic plasticity of S. frugiperda , delaying the selection of resistant biotypes and consolidating neem as a cornerstone for IPM sustainability across different altitudinal zones. This multicomponent synergistic action explains the greater efficacy of crude A. indica oil over purified azadirachtin. In field conditions, efficacy ranges between 40% and 85% damage reduction in Z. mays crops, conditioned primarily by the larval instar at the time of application, the environmental stability of the formulation, and the use of adjuvants. Emerging nanoformulations — microencapsulation, chitosan nanocomposites — represent a technological priority for overcoming the photolability limitation of conventional EC formulations, with demonstrated improvements in half-life and efficacy in both laboratory and semi-field conditions. Key knowledge gaps identified include: (i) scarcity of field studies in high-altitude Andean ecosystems with S. frugiperda ; (ii) insufficient field evidence for emerging formulations (nanotechnology, microencapsulation); (iii) absence of complete molecular characterization of the ontogenetic resistance of S. frugiperda to neem oil through comparative transcriptomics across all six larval instars; and (iv) the need for studies integrating the effect of the complete phytochemical complex of neem — including margolones, catechins, and amide alkaloids — on pest population dynamics in the field. Declarations Author contributions: HGV: conceptualization, investigation, writing and editing. 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Functional Ecology , 25(2), 325–338. https://doi.org/10.1111/j.1365-2435.2010.01801.x Schmutterer, H. (1990). Properties and potential of natural pesticides from the neem tree, Azadirachta indica . Annual Review of Entomology , 35, 271–297. https://doi.org/10.1146/annurev.en.35.010190.001415 Senthil-Nathan, S. (2013). Physiological and biochemical effect of neem and other Meliaceae plants secondary metabolites against Lepidopteran insects. Frontiers in Physiology , 4, 359. https://doi.org/10.3389/fphys.2013.00359 Siddiqui, B. S., Afshan, F., Ghiasuddin, Faizi, S., Naqvi, S. N. H., & Tariq, R. M. (2004). Two new triterpenoids and a sterol from the leaves of Azadirachta indica . Phytochemistry , 65(16), 2363–2367. https://doi.org/10.1016/j.phytochem.2004.07.017 Silva-Brandão, K. L., Barros-Nunes, L. A., Cônsoli, F. L., Zotti, M. J., Sosa-Gomez, D. R., & Nava, D. E. (2024). Population genomics of Spodoptera frugiperda (Lepidoptera: Noctuidae) in Brazil and its implications for resistance management. Evolutionary Applications , 17(3), e13659. https://doi.org/10.1111/eva.13659 Simmonds, M. S. J. (2001). Importance of flavonoids in insect-plant interactions: feeding and oviposition. Phytochemistry , 56(3), 245–252. https://doi.org/10.1016/S0031-9422(00)00451-5 Smirle, M. J., Lowery, D. T., & Isman, M. B. (1996). Toxicity of neem extracts to Spodoptera litura : effects of temperature and formulation. Journal of Economic Entomology , 89(1), 140–144. https://doi.org/10.1093/jee/89.1.140 Sparks, T. C., & Nauen, R. (2015). IRAC: Insecticide resistance, and mode of action classification of insecticides. Pesticide Biochemistry and Physiology , 121, 122–128. https://doi.org/10.1016/j.pestbp.2014.11.014 Stark, J. D., & Walter, J. F. (1995). Persistence of azadirachtin A and B in soil: Effects of temperature and microbial activity. Journal of Environmental Science and Health, Part B , 30(5), 685–698. https://doi.org/10.1080/03601239509372958 Sun, X. X., Hu, C. X., Jia, H. R., Wu, Q. L., Shen, X. J., Zhao, S. Y., Jiang, Y. Y., & Wu, K. M. (2021). Case study on the first immigration of fall armyworm Spodoptera frugiperda invading into China. Journal of Integrative Agriculture , 20(3), 664–672. https://doi.org/10.1016/S2095-3119(19)62839-X Tay, W. T., Meagher, R. L., Jr., Czepak, C., & Groot, A. T. (2023). Spodoptera frugiperda : ecology, evolution, and management options of an invasive species. Annual Review of Entomology , 68(1), 299–317. https://doi.org/10.1146/annurev-ento-120220-105416 Viana, P. A., & Prates, H. T. (2003). Desenvolvimento e mortalidade larval de Spodoptera frugiperda em folhas de milho tratadas com extrato aquoso de folhas de nim ( Azadirachta indica ). Bragantia , 62(1), 69–74. https://doi.org/10.1590/S0006-87052003000100009 Wang, J., Wang, H., Liu, S., Liu, L., Tay, W. T., Walsh, T. K., Yang, Y., & Wu, Y. (2023). Genome-wide transcriptional analysis reveals the molecular basis of developmental stage-related insecticide tolerance in fall armyworm Spodoptera frugiperda . Pest Management Science , 79(8), 2883–2895. https://doi.org/10.1002/ps.7471 Wu, H., Lin, Y.-G., Du, P.-R., Hou, R.-Q., Zeeshan, M., Xu, H.-H., & Zhang, Z.-X. (2025). O-Carboxymethyl chitosan-based azadirachtin enhances anti-degradation properties of azadirachtin and antifeedant activity against Spodoptera frugiperda . Pest Management Science . https://doi.org/10.1002/ps.70373 Zhang, X., Liu, Y., He, Q., Yang, Z., & Li, F. (2023). Transcriptome analysis reveals immune-related genes and pathways in Spodoptera frugiperda midgut after oral infection with Bacillus thuringiensis . Frontiers in Microbiology , 14, 1156304. https://doi.org/10.3389/fmicb.2023.1156304 Additional Declarations The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9361769","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":619952327,"identity":"869c38fd-8d6b-4419-945e-95673bafab65","order_by":0,"name":"Humberto Giraldo-Vanegas","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-0801-2714","institution":"Universidad de Pamplona","correspondingAuthor":true,"prefix":"","firstName":"Humberto","middleName":"","lastName":"Giraldo-Vanegas","suffix":""},{"id":619952328,"identity":"24bbe9b3-f7f8-494f-bdae-a23b7bfa1439","order_by":1,"name":"Gabriel Giraldo-Herrera","email":"","orcid":"https://orcid.org/0009-0005-1192-0069","institution":"Universidad de Pamplona","correspondingAuthor":false,"prefix":"","firstName":"Gabriel","middleName":"","lastName":"Giraldo-Herrera","suffix":""}],"badges":[],"createdAt":"2026-04-09 01:18:39","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9361769/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9361769/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106585222,"identity":"414cd507-81ad-41d3-bf5b-a8833654d5cb","added_by":"auto","created_at":"2026-04-10 07:29:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1411652,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9361769/v1/9b6e292e-7cc8-4f73-baca-db36a0c1af1f.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eUse of Oil, Aqueous Extracts, and Formulations of \u003c/strong\u003e\u003cem\u003eAzadirachta indica\u003c/em\u003e\u003cstrong\u003e A. Jussieu against \u003c/strong\u003e\u003cem\u003eSpodoptera frugiperda\u003c/em\u003e\u003cstrong\u003e: A Systematic Review (2015–2026)\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003e1.1. Spodoptera frugiperda (J. E. Smith): Biology, Global Expansion, and Economic Impact\u003c/h2\u003e \u003cp\u003e \u003cem\u003eSpodoptera frugiperda\u003c/em\u003e (J. E. Smith) (Lepidoptera: Noctuidae) is recognized as one of the most economically important agricultural pests on a global scale (Montezano et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Tay et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). This polyphagous lepidopteran, native to tropical and subtropical regions of the Americas, has the capacity to attack more than 400 plant species, with a marked preference for agronomically important grasses such as maize [\u003cem\u003eZea mays\u003c/em\u003e L.], sorghum [\u003cem\u003eSorghum bicolor\u003c/em\u003e (L.) Moench], rice [\u003cem\u003eOryza sativa\u003c/em\u003e L.], and cotton (\u003cem\u003eGossypium hirsutum\u003c/em\u003e L.) (Casmuz et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Early et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Yield losses in maize attributable to \u003cem\u003eS. frugiperda\u003c/em\u003e are estimated at 18\u0026ndash;30% of global production, representing billions of dollars annually (Montezano et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Machekano et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSince its first detection outside the Americas in West Africa in 2016, \u003cem\u003eS. frugiperda\u003c/em\u003e dispersed to 44 African countries within three years, reaching the Asian continent between 2018 and 2019 \u0026mdash; India, China, Thailand, Myanmar, Bangladesh, and Sri Lanka \u0026mdash; and Australia in 2020 (Goergen et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Ganiger et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Sun et al., \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In China, associated economic losses are estimated at USD 2.46\u0026ndash;6.18\u0026nbsp;billion annually (Liu et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Its biological characteristics \u0026mdash; high fecundity (1,000\u0026ndash;1,500 eggs per female), short life cycle (30\u0026ndash;40 days), and flight capacity of up to 100 km per night \u0026mdash; favor its persistence as a transboundary pest (Tay et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eControl of \u003cem\u003eS. frugiperda\u003c/em\u003e has historically depended on intensive use of synthetic organophosphate, pyrethroid, and carbamate insecticides. However, high-level resistance (\u0026gt;\u0026thinsp;100\u0026times;) has been documented in populations from Brazil, Puerto Rico, Mexico, and several Asian countries (Carvalho et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Guti\u0026eacute;rrez-Moreno et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Silva-Brand\u0026atilde;o et al., \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). The use of Cry proteins from \u003cem\u003eBacillus thuringiensis\u003c/em\u003e Berliner in transgenic cultivars has also generated field-level resistance (Boaventura et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Nascimento et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Against this backdrop, the development of sustainable biorational alternatives within Integrated Pest Management (IPM) has become a priority in applied entomological research (Isman, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Pavela \u0026amp; Benelli, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.2. Azadirachta indica A. Jussieu: Secondary Metabolites and Insecticidal Activity\u003c/h2\u003e \u003cp\u003eThe neem tree, \u003cem\u003eAzadirachta indica\u003c/em\u003e A. Jussieu (Meliaceae), contains more than 200 bioactive compounds distributed in four major groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e): (i) tetranortriterpene limonoids, of which the most active is azadirachtin A (C₃₅H₄₄O₁₆, MW\u0026thinsp;=\u0026thinsp;720.7 g/mol, 16 stereocenters); (ii) secondary limonoids such as salannin (C₃₄H₄₄O₉), nimbin (C₃₀H₃₆O₉), gedunin (C₂₈H₃₄O₇), and azadiradione (C₂₈H₃₄O₄); (iii) flavonoids and polyphenols (catechin, epicatechin, quercetin, kaempferol) and diterpenoids (margolones); and (iv) the phytosterol β-sitosterol (C₂₉H₅₀O) and the fatty acids oleic and linoleic acids, which are the major components of seed oil (Schmutterer, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; Mordue \u0026amp; Nisbet, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Koul, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2004\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAzadirachtin A exerts a multimodal insecticidal action including: (i) ecdysteroid and juvenile hormone antagonism through interference with the nuclear receptors EcR/USP and Met/FISC; (ii) feeding inhibition by blockade of gustatory chemoreceptors; (iii) intestinal cytotoxicity through apoptosis of epithelial cells; and (iv) immunotoxicity with suppression of phenoloxidase (PO) and cellular encapsulation (Mordue \u0026amp; Blackwell, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; Mordue et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Kumar et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). This multi-target mechanism significantly reduces the risk of resistance development in \u003cem\u003eS. frugiperda\u003c/em\u003e compared with single-site synthetic insecticides (Isman, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Sparks \u0026amp; Nauen, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e1.3. Review Objectives\u003c/h2\u003e \u003cp\u003eThe primary objective of this review is to critically and systematically analyze the scientific evidence published between 2015 and 2026 on the use of oil, aqueous extracts, and formulations of \u003cem\u003eA. indica\u003c/em\u003e against \u003cem\u003eS. frugiperda\u003c/em\u003e (J. E. Smith) under laboratory and field conditions (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e), integrating knowledge on the multi-target modes of action of its metabolites (Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) to inform recommendations for IPM programs. As a secondary objective, the influence of high-altitude climatic conditions on formulation efficacy and the pest's ecophysiology is examined.\u003c/p\u003e \u003c/div\u003e"},{"header":"2. Bibliographic Search Methodology","content":"\u003cp\u003eThe bibliographic search was conducted in the Scopus, Web of Science, PubMed, Google Scholar, SciELO, and AGRIS databases, covering publications from January 2015 to March 2026. Search terms employed, combined using Boolean operators (AND, OR, NOT), included: \"\u003cem\u003eSpodoptera frugiperda\u003c/em\u003e\", \"neem\", \"\u003cem\u003eAzadirachta indica\u003c/em\u003e\", \"azadirachtin\", \"neem oil\", \"NSKE\", \"botanical insecticide\", \"biopesticide\", \"fall armyworm control\", and their Spanish equivalents. Original research articles, systematic reviews, and indexed postgraduate theses published between 2015 and 2026 were included. Studies without access to full text, without quantitative efficacy results, or involving species other than \u003cem\u003eS. frugiperda\u003c/em\u003e or formulations other than \u003cem\u003eA. indica\u003c/em\u003e were excluded. Of 187 references initially identified, 68 met inclusion criteria. The 28 most representative studies and reviews are synthesized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e"},{"header":"3. Results and Discussion","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Studies on the Use of Azadirachta indica against Spodoptera frugiperda\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e synthesizes the studies and reviews identified that evaluated the use of \u003cem\u003eA. indica\u003c/em\u003e formulations against \u003cem\u003eS. frugiperda\u003c/em\u003e between 1990 and 2026. Of the total, ten correspond to laboratory trials, six to field or mixed (laboratory/field) trials, and seven to bibliographic reviews. Geographically, studies are concentrated in Latin America (Ecuador, Mexico, Nicaragua, Colombia), Asia (India, China), Africa (Zimbabwe, Botswana, South Africa), and Europe (Italy, Czech Republic). Formulations comprise emulsifiable concentrate (EC) oil, neem seed kernel extract (NSKE), technically purified azadirachtin, and emerging nanotechnology-based formulations.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudies on the use of \u003cem\u003eAzadirachta indica\u003c/em\u003e A. Jussieu formulations against \u003cem\u003eSpodoptera frugiperda\u003c/em\u003e (J. E. Smith) under laboratory and field conditions (1990\u0026ndash;2026).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor(s)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFormulation/Product\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eType\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSetting\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCountry/Region\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMain finding\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSchmutterer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1990\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOil, botanical extracts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFoundational characterization of neem chemistry and insecticidal activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMordue \u0026amp; Blackwell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1993\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePurified azadirachtin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAzadirachtin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUnited Kingdom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eElucidated multi-target mode of action of azadirachtin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGarc\u0026iacute;a et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeem botanical extract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAqueous extract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eField\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eColombia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eField efficacy against S. frugiperda in maize\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMordue \u0026amp; Nisbet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePurified azadirachtin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAzadirachtin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUnited Kingdom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eComprehensive review of azadirachtin action in insects\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNathan et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeem limonoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAqueous extract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLimonoid activity on vector mosquito Anopheles stephensi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharleston et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eA. indica\u003c/em\u003e\u0026thinsp;+\u0026thinsp;\u003cem\u003eM. azedarach\u003c/em\u003e extract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAqueous extract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eField\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSouth Africa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eImpact on Plutella xylostella populations and natural enemies\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsman\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBotanical insecticides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGlobal overview of botanical insecticides in modern agriculture\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGuti\u0026eacute;rrez et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFormulated neem oil (EC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFormulated oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLab/Field\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMexico\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLC₅₀ = 720\u0026ndash;950 \u0026micro;L/L for L3\u0026ndash;L5 at 22\u0026deg;C\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSenthil-Nathan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMeliaceae extracts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAqueous extract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLab/Review\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBiochemical effects of neem limonoids on Lepidoptera\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsman\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBotanical insecticides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRenaissance of botanical insecticides and regulatory outlook\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCampos et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeem oil, NSKE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOil/NSKE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNeem oil in crop protection: current status and future\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsman\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBotanical insecticides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21st-century botanical insecticides: innovation and going green\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlmeida\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeem oil\u0026thinsp;+\u0026thinsp;vegetable oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFormulated oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEcuador\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLarvicidal efficacy in maize against S. frugiperda\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG\u0026aacute;mez\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBotanical extract (neem, \u003cem\u003eEucalyptus\u003c/em\u003e spp., \u003cem\u003eCapsicum annuum\u003c/em\u003e L.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAqueous extract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNicaragua\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMortality 58\u0026ndash;78% (NSKE 5%) and 80\u0026ndash;88% (NSKE 10%) in L2\u0026ndash;L4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL\u0026oacute;pez et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEC oil\u0026thinsp;+\u0026thinsp;NSKE 3\u0026ndash;10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOil/NSKE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLab+Field\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEcuador\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLC₅₀ = 650\u0026ndash;840 \u0026micro;L/L for L2\u0026ndash;L4; antifeedant effect 65\u0026ndash;75%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePavela \u0026amp; Benelli\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEssential oils and neem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCzech Rep./Italy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eChallenges of botanical insecticides as ecofriendly biopesticides\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCantrell et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNatural products as pesticides (incl. neem)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOpportunities and constraints for natural product pesticides\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKumar et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOil, extracts, limonoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOil/extract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNeem potential for animal and human health safeguarding\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMachekano et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCommercial neem formulations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFormulated oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eField/Review\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAfrica (Zimbabwe, Botswana)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFAW biology, ecology, genetic diversity and management in Africa\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBezerra et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMicroencapsulated/photoresistant \u003cem\u003eA. indica\u003c/em\u003e extract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEmerging form.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLab/Semi-field\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eExtended half-life and improved efficacy against S. frugiperda under semi-field conditions\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHarrison et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAgroecological options incl. neem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eField/Review\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSub-Saharan Africa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFAW management options; neem as low-cost smallholder-friendly solution\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePavela et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBotanical insecticides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReview\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCzech Rep./Italy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCriteria for biopesticide commercialization in the 21st century\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWu et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO-carboxymethyl chitosan-azadirachtin nanoformulation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEmerging form.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNanoformulation improves azadirachtin stability; enhanced antifeedant against S. frugiperda\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCa\u0026ntilde;as-Meaury et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeemAZAL\u0026reg; 1.2% EC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFormulated oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eColombia (Pamplona)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eInstar-specific larvicidal efficacy at 2,586 m a.s.l.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReatiga-Pulido et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeemAZAL\u0026reg; 1.2% EC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFormulated oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eColombia (Pamplona)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eInstar toxicity analysis under high-altitude laboratory conditions\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGiraldo-Vanegas et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2026a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeemAZAL\u0026reg; 1.2% EC \u0026mdash; dose-response and survival analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFormulated oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eColombia (Pamplona)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLC₅₀ = 579.67\u0026ndash;921.36 \u0026micro;L/L across L1\u0026ndash;L6; R\u0026sup2; = 0.94\u0026ndash;0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGiraldo-Vanegas et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2026b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeemAZAL\u0026reg; 1.2% EC \u0026mdash; ontogenetic thresholds and LT dynamics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFormulated oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eColombia (Pamplona)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLT₅₀ = 52.39 h (L1) to 196.69 h (L5); 271.3% ontogenetic gradient\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eNote.\u003c/em\u003e EC\u0026thinsp;=\u0026thinsp;emulsifiable concentrate; NSKE\u0026thinsp;=\u0026thinsp;Neem Seed Kernel Extract; Lab. = laboratory; Rev. = bibliographic review; a.s.l. = above sea level. Source: compiled by the authors.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe analysis of Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e reveals a sustained increase in publications from 2020 onward, coinciding with the global expansion of \u003cem\u003eS. frugiperda\u003c/em\u003e to Asia and Oceania. The works of Giraldo-Vanegas et al. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2026a\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003eb\u003c/span\u003e), Ca\u0026ntilde;as-Meaury et al. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), and Reatiga-Pulido et al. (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), conducted under high-altitude conditions in Pamplona, Norte de Santander, Colombia (2,586 m a.s.l., 17\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026deg;C), are the only studies that simultaneously evaluate all six larval instars of \u003cem\u003eS. frugiperda\u003c/em\u003e with formulated azadirachtin, constituting the most ontogenetically comprehensive works available for the Colombian Andean region.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Phytochemical Characterization of the Defensive Complex of Azadirachta indica\u003c/h2\u003e \u003cp\u003eThe efficacy of neem formulations against \u003cem\u003eS. frugiperda\u003c/em\u003e does not reside in a single active ingredient, but in the synergy of diverse chemical families (Koul, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Schmutterer, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e). More than 20 target metabolites form the core of the biological activity, classified into four main groups: limonoids and triterpenoids, phytosterols and amide alkaloids, oxygenated diterpenoids, and the flavonoid-polyphenol complex (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrincipal secondary metabolites of \u003cem\u003eAzadirachta indica\u003c/em\u003e A. Jussieu with documented biological activity against insect pests.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetabolite\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMol. formula\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMW (g/mol)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCAS No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePlant part\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePrimary biological activity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAzadirachtin A\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₃₅H₄₄O₁₆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e720.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11141-17-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEcdysteroid antagonism, antifeedant (60\u0026ndash;90%), intestinal cytotoxicity, immunosuppression, CYP/GST inhibition\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAzadirachtin B\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₃₅H₄₄O₁₆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e720.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11141-17-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIsomer B; lower biological activity than A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSalannin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₃₄H₄₄O₉\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e596.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e992-20-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePotent antifeedant; immediate action on gustatory chemoreceptors\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNimbin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₃₀H₃₆O₉\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e556.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13030-24-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed, bark\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eImmunosuppressant; antifungal; synergist with azadirachtin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eGedunin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₂₈H₃₄O₇\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e482.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2753-30-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHsp90 inhibitor; amplifies EcR disruption; antimalarial\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAzadiradione\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₂₈H₃₄O₄\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e450.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18472-36-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed, leaf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eContact insecticide; cuticle disruption; antibacterial\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eβ-Sitosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₂₉H₅₀O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e414.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83-46-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCompetitive antagonist EcR/USP receptor; analog of 20-HE\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eQuercetin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₅H₁₀O₇\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e302.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e117-39-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLeaf, bark\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCYP P450 and GST inhibitor; pro-oxidant; antibacterial\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eKaempferol\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₅H₁₀O₆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e286.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e520-18-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLeaf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCo-inhibitor CYP P450; antifungal; synergist with azadirachtin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOleic acid (18:1 Δ⁹-cis)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₈H₃₄O₂\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e282.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e112-80-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePrimary lipid vehicle (50\u0026ndash;60%); enhances transdermal penetration of azadirachtin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLinoleic acid (18:2 Δ⁹,\u0026sup1;\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₈H₃₂O₂\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e280.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60-33-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCo-vehicle (15\u0026ndash;20%); generates LOOHs under UV \u0026rarr; secondary oxidative stress\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSalannol\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₃₂H₄₄O₈\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e564.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78012-51-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eComplementary limonoid; synergistic antifeedant\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNimbinene\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₂₈H₃₄O₇\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e482.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78916-54-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHigh lipophilicity; synergistic activity with azadirachtin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNimbolin A\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₃₉H₄₆O₈\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e650.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24480-41-9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAntagonistic interactions with digestive enzymes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAzadiramide A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmide alkaloid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo universal CAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLeaf, seed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNeurotoxic properties; characterized by NMR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMargolone\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₉H₂₄O₃\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e300.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e120092-48-0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTricyclic diterpenoid; intestinal epithelium cytotoxicity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMargolonone\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₉H₂₂O₄\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e314.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e120092-49-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSeed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOxidized derivative; lipid homeostasis disruption\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003e(+)-Catechin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₅H₁₄O₆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e290.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e154-23-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLeaf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCYP P450 and GST inhibition (trans configuration); synergistic oxidative stress\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003e(\u0026minus;)-Epicatechin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₅H₁₄O₆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e290.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e490-46-0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLeaf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIsomer (cis); co-inhibitor of detoxification systems\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cem\u003eNote.\u003c/em\u003e MW\u0026thinsp;=\u0026thinsp;molecular weight; CAS\u0026thinsp;=\u0026thinsp;Chemical Abstracts Service; 20-HE\u0026thinsp;=\u0026thinsp;20-hydroxyecdysone; EcR/USP\u0026thinsp;=\u0026thinsp;ecdysone receptor/ultraspiracle protein; LOOHs\u0026thinsp;=\u0026thinsp;lipid hydroperoxides. Source: compiled by the authors after Schmutterer (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e), Mordue \u0026amp; Nisbet (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2000\u003c/span\u003e), Koul (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2004\u003c/span\u003e), and Nicoletti et al. (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e3.2.1. Limonoids and Triterpenoids\u003c/h2\u003e \u003cp\u003eTetranortriterpenoids constitute the most potent biological markers of neem, characterized by a highly oxygenated fused ring system (Kraus, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e1995\u003c/span\u003e; Schmutterer, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e). Azadirachtin A (C₃₅H₄₄O₁₆, CAS 11141-17-6) presents a pentacyclic skeleton (rings A\u0026ndash;B\u0026ndash;C\u0026ndash;D\u0026ndash;E) with 16 stereocenters. Salannin (C₃₄H₄₄O₉), a seco-limonoid with an open B ring, exhibits antifeedant potency superior to azadirachtin A at equivalent concentrations. Salannol (C₃₂H₄₄O₈), nimbinene (C₂₈H₃₄O₇), and nimbolin A (C₃₉H₄₆O₈) complement the limonoid profile with antagonistic interactions on insect digestive enzymes and chemoreceptors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e3.2.2. Phytosterols, Amide Alkaloids, and Diterpenoids\u003c/h2\u003e \u003cp\u003eβ-Sitosterol (C₂₉H₅₀O, CAS 83-46-5), present at 0.8\u0026ndash;1.2% of seed oil, acts as a competitive antagonist of 20-hydroxyecdysone (20-HE) for the nuclear receptor EcR/USP (Behmer \u0026amp; Nes, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). Azadiramide A, an amide alkaloid characterized by NMR in leaves and seeds, exhibits neurotoxic properties (Siddiqui et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Margolones (C₁₉H₂₄O₃ and C₁₉H₂₂O₄, CAS 120092-48-0 and 120092-49-1) are tricyclic diterpenoids associated with cytotoxicity in the intestinal epithelium and disruption of larval lipid homeostasis (Koul, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2004\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e3.2.3. Flavonoid and Polyphenolic Complex\u003c/h2\u003e \u003cp\u003eFlavonoids are fundamental for the inhibition of detoxification systems and the generation of oxidative stress in polyphagous insects (Salminen \u0026amp; Karonen, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Simmonds, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). Quercetin (C₁₅H₁₀O₇, CAS 117-39-5) and kaempferol (C₁₅H₁₀O₆, CAS 520-18-3), present in leaves of \u003cem\u003eA. indica\u003c/em\u003e, competitively inhibit CYP6 and CYP9 monooxygenases and glutathione-S-transferases (GSTs). (+)-Catechin (C₁₅H₁₄O₆, CAS 154-23-4) and (\u0026minus;)-epicatechin (C₁₅H₁₄O₆, CAS 490-46-0) differ in the relative configuration of C2\u0026ndash;C3 carbons (trans and cis, respectively), which determines variations in their affinity for detoxification enzymes. Both flavanols synergize with the limonoids of crude oil, incapacitating the insect from neutralizing the toxic complex (Riaz et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Formulation Efficacy under Laboratory Conditions\u003c/h2\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e3.3.1. Acute Toxicity Parameters: LC₅₀ and LT₅₀\u003c/h2\u003e \u003cp\u003eNeem oil formulated as an emulsifiable concentrate (EC) with azadirachtin A content between 0.5% and 3% has demonstrated significant insecticidal activity against the different larval instars of \u003cem\u003eS. frugiperda\u003c/em\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e). L\u0026oacute;pez et al. (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) determined, through Probit analysis, LC₅₀ values of 650\u0026ndash;840 \u0026micro;L/L for L2\u0026ndash;L4 larvae in Ecuador (25\u0026deg;C; R\u0026sup2; = 0.93\u0026ndash;0.95). Guti\u0026eacute;rrez et al. (2010) reported LC₅₀ values of 720\u0026ndash;950 \u0026micro;L/L for L3\u0026ndash;L5 in Mexico (22\u0026deg;C), and G\u0026aacute;mez (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) obtained 590\u0026ndash;780 \u0026micro;L/L for L1\u0026ndash;L3 in Nicaragua (27\u0026deg;C).\u003c/p\u003e \u003cp\u003eGiraldo-Vanegas et al. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2026a\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003eb\u003c/span\u003e) determined the toxicological parameters of NeemAZAL\u0026reg; 1.2% EC for all six larval instars of \u003cem\u003eS. frugiperda\u003c/em\u003e under Colombian high-altitude conditions, obtaining Probit models with R\u0026sup2; = 0.94\u0026ndash;0.95. LC₅₀ values ranged from 579.67 \u0026micro;L/L (L1) to 921.36 \u0026micro;L/L (L6), with a 58.9% increase in the required concentration from first to sixth instar, adjustable to the model: LC₅₀ = 472.8\u0026thinsp;+\u0026thinsp;74.3 \u0026times; instar (R\u0026sup2; = 0.986; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The LT₅₀ was 52.39 h for L1, increasing to 196.69 h in L5 (271.3% increment). This ontogenetic susceptibility gradient is grounded in: (i) progressive cuticle thickening (~\u0026thinsp;2 \u0026micro;m in L1 to ~\u0026thinsp;15 \u0026micro;m in L6); (ii) a 4.2\u0026ndash;6.8-fold increase in CYP6/CYP9 expression between L1 and L5 (Huang et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); (iii) toxicokinetic dilution due to body mass increase (~\u0026thinsp;89-fold between L1 and L6); and (iv) a robust cellular immune response in advanced instars (Lavine \u0026amp; Strand, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2002\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.3.2. Sublethal Effects on Biological Parameters\u003c/h2\u003e \u003cp\u003eBeyond direct mortality, \u003cem\u003eA. indica\u003c/em\u003e formulations exert significant sublethal effects. At sublethal concentrations (LC₂₅\u0026ndash;LC₁₀), reductions in foliar consumption of 55\u0026ndash;72% and weight gain of 40\u0026ndash;65% are documented in L2\u0026ndash;L4 larvae (Schmutterer, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; L\u0026oacute;pez et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Exposure of L5\u0026ndash;L6 larvae to 500\u0026ndash;800 \u0026micro;L/L of formulated azadirachtin results in frequencies of malformed pupae of 20\u0026ndash;45% and adults with deformed wings of 15\u0026ndash;30%. Almeida (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) reported a reduction in fecundity of 20\u0026ndash;35% and egg viability of 15\u0026ndash;40% in adults emerging from treated larvae, evidencing transgenerational effects (Isman, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Pavela \u0026amp; Benelli, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Aqueous Extracts and Emerging Formulations\u003c/h2\u003e \u003cp\u003eNeem seed kernel extract (NSKE) at 5% is one of the most studied formulations due to its low cost and availability (Campos et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Isman, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). G\u0026aacute;mez (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) reported mortalities of 58\u0026ndash;78% at 72 h with NSKE at 5% in L2\u0026ndash;L4 larvae. L\u0026oacute;pez et al. (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) demonstrated that NSKE at 10% achieved mortalities of 80\u0026ndash;88% at 96 h, statistically equivalent to those of formulated oil at 1.0 mL/L, with antifeedant effects of 65\u0026ndash;75% even at 3%. Extracts of \u003cem\u003eA. indica\u003c/em\u003e leaves, with contributions of nimbin (C₃₀H₃₆O₉) and gedunin (C₂₈H₃₄O₇), show mortalities of 45\u0026ndash;65% in L1\u0026ndash;L2 at concentrations of 10% in water (Machekano et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEmerging formulations \u0026mdash; nanoemulsions, microencapsulated azadirachtin, and chitosan-azadirachtin nanocomposites \u0026mdash; present LC₅₀ values up to 2.5-fold lower and extended environmental half-lives of 7\u0026ndash;21 days compared with conventional EC formulations (Bezerra et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Wu et al., \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Wu et al. (\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) demonstrated that O-carboxymethyl chitosan-based azadirachtin nanoformulations substantially improve the anti-degradation properties of azadirachtin and significantly enhance antifeedant activity against \u003cem\u003eS. frugiperda\u003c/em\u003e, representing a major advance in the field of neem-based biopesticide technology. Cantrell et al. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) place these developments within the broader framework of natural product-based pesticide innovation, underscoring the importance of precision delivery systems in overcoming the photolability limitations of azadirachtin.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Field Efficacy\u003c/h2\u003e \u003cp\u003eField studies report efficacies of formulated neem oil (1.0\u0026ndash;2.0 mL/L) of 40\u0026ndash;85% reduction in foliage damage in \u003cem\u003eZ. mays\u003c/em\u003e crops (Guti\u0026eacute;rrez et al., 2010; L\u0026oacute;pez et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Machekano et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Harrison et al. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), in a review of sub-Saharan African trials, found that applications directed at L1\u0026ndash;L2 achieved damage reductions of 65\u0026ndash;85%, while late applications on L4\u0026ndash;L6 showed efficacies of 30\u0026ndash;50%. Photodegradation of azadirachtin A under direct solar radiation reduces its half-life to 1\u0026ndash;4 days, requiring applications every 5\u0026ndash;7 days to maintain acceptable control levels (Stark \u0026amp; Walter, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e1995\u003c/span\u003e; Barrek et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). In high-altitude Andean agroecosystems, Giraldo-Vanegas et al. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2026a\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003eb\u003c/span\u003e) employed applications at 5\u0026ndash;7-day intervals, evidencing the technical necessity of UV-protective microemulsions or co-adjuvants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e3.6. Multi-Target Modes of Action\u003c/h2\u003e \u003cp\u003eThe metabolites of \u003cem\u003eA. indica\u003c/em\u003e act on \u003cem\u003eS. frugiperda\u003c/em\u003e through complementary biochemical mechanisms that affect multiple insect systems simultaneously or sequentially (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This multi-target attack strategy saturates the phenotypic plasticity of the pest, minimizing the selection of resistant biotypes (Isman, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Sparks \u0026amp; Nauen, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMode of action of principal metabolites of \u003cem\u003eAzadirachta indica\u003c/em\u003e A. Jussieu on \u003cem\u003eSpodoptera frugiperda\u003c/em\u003e (J. E. Smith) (Lepidoptera: Noctuidae).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetabolite\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMol. formula\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTarget / Site of action\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMechanism and main effect\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eInstar\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReferences\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAzadirachtin A\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₃₅H₄₄O₁₆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEcR/USP and Met/FISC receptors; gustatory chemoreceptors; intestinal epithelium; hemocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEcdysteroid antagonism (molting blockage); antifeedant 60\u0026ndash;90% ingesta; intestinal apoptosis; \u0026darr;PO; downregulates CYP6/CYP9/GSTs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL1\u0026ndash;L6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMordue \u0026amp; Blackwell, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; Kumar et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Giraldo-Vanegas et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2026a\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2026b\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSalannin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₃₄H₄₄O₉\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChemoreceptor deterrent neurons (maxillary palps)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eImmediate antifeedant (minutes); nanomolar EC₅₀; \u0026darr;foliar consumption 65\u0026ndash;90% in L2\u0026ndash;L4; no systemic absorption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL2\u0026ndash;L4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMordue \u0026amp; Blackwell, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; Senthil-Nathan, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; L\u0026oacute;pez et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNimbin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₃₀H₃₆O₉\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHemocytes (PO, antimicrobial peptides); peritrophic membrane\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eImmunosuppression: \u0026darr;PO; \u0026uarr;peritrophic permeability; facilitates secondary penetration of azadirachtin into hemocoel (L3\u0026ndash;L5); synergist\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL3\u0026ndash;L5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSchmutterer, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; Senthil-Nathan, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Machekano et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2024\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eGedunin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₂₈H₃₄O₇\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHsp90 (N-terminal/ATP domain); EcR receptor; fat body\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInhibits Hsp90 \u0026rarr; ubiquitin-proteasome degradation of EcR complex; amplifies molting disruption in L3\u0026ndash;L5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL3\u0026ndash;L5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSenthil-Nathan, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Kumar et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2024\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAzadiradione\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₂₈H₃₄O₄\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEpicuticular membrane (contact); intestinal microbiome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eContact insecticide: cuticle disruption (log P\u0026thinsp;\u0026asymp;\u0026thinsp;4.2); broad-spectrum antibacterial on midgut microbiome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL1\u0026ndash;L6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSchmutterer, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; Campos et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2016\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eβ-Sitosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₂₉H₅₀O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEcR/USP receptor; midgut lipid membrane domains\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCompetitive antagonism of 20-HE; saturates ecdysteroid signaling; interferes with membrane biosynthesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL1\u0026ndash;L6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSchmutterer, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; Behmer \u0026amp; Nes, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2003\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eQuercetin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₅H₁₀O₇\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCYP6/CYP9 (phase I); GSTs (phase II); hemocyte mitochondria; microbiome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026uarr;azadirachtin half-life 15\u0026ndash;30%; caspase-3/9 apoptosis at \u0026gt;\u0026thinsp;100 \u0026micro;M; bacteriostatic on intestinal microbiome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL2\u0026ndash;L5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHuang et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Simmonds, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2001\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eKaempferol\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₅H₁₀O₆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCYP P450; intestinal microbiome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCo-inhibits CYP P450; antifungal on microbiome; synergist with azadirachtin in L2\u0026ndash;L4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL2\u0026ndash;L4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSenthil-Nathan, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2013\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOleic acid (Δ⁹-cis)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₈H₃₄O₂\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEpicuticular surface lipids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePrimary lipid vehicle (50\u0026ndash;60%); Δ⁹-cis geometry improves transcuticular diffusion of azadirachtin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL1\u0026ndash;L6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCampos et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2016\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLinoleic acid (Δ⁹,\u0026sup1;\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₈H₃₂O₂\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEpicuticular surface; contact membranes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCo-vehicle (15\u0026ndash;20%); generates LOOHs under UV \u0026rarr; secondary oxidative stress on cuticle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL1\u0026ndash;L6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCampos et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2016\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCatechin/Epicatechin\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₅H₁₄O₆\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCYP P450; GSTs; peritrophic membrane\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInhibition of detoxification phase I and II enzymes; synergistic oxidative stress\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL2\u0026ndash;L5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRiaz et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Salminen \u0026amp; Karonen, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2011\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMargolones\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC₁₉H₂₄/₂₂O₃/₄\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIntestinal epithelium; lipid membrane domains\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCytotoxicity in midgut mesenterone; peritrophic membrane destruction; lipid homeostasis disruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eL1\u0026ndash;L4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSchmutterer, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; Koul, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2004\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cem\u003eNote.\u003c/em\u003e EcR/USP\u0026thinsp;=\u0026thinsp;ecdysone receptor/ultraspiracle protein; Met/FISC\u0026thinsp;=\u0026thinsp;juvenile hormone receptor; PO\u0026thinsp;=\u0026thinsp;phenoloxidase; CYP\u0026thinsp;=\u0026thinsp;cytochrome P450; GSTs\u0026thinsp;=\u0026thinsp;glutathione-S-transferases; LOOHs\u0026thinsp;=\u0026thinsp;lipid hydroperoxides; 20-HE\u0026thinsp;=\u0026thinsp;20-hydroxyecdysone; Hsp90\u0026thinsp;=\u0026thinsp;90 kDa chaperone protein. Source: compiled by the authors.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e3.6.1. Azadirachtin A: Neuroendocrine Antagonism and Cytotoxicity\u003c/h2\u003e \u003cp\u003eAzadirachtin A (C₃₅H₄₄O₁₆, MW\u0026thinsp;=\u0026thinsp;720.7 g/mol) acts through four principal mechanisms on \u003cem\u003eS. frugiperda\u003c/em\u003e: (i) \u003cem\u003eneuroendocrine antagonism\u003c/em\u003e, competing with 20-HE and juvenile hormone (JH-III) for the nuclear receptors EcR/USP and Met/FISC, blocking early ecdysis genes (E74, Broad-Complex, HR3) and preventing synthesis of new cuticle, generating exuvia retention and mortality during ecdysis (Mordue \u0026amp; Blackwell, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; Martinez \u0026amp; van Emden, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2001\u003c/span\u003e); (ii) \u003cem\u003efeeding inhibition\u003c/em\u003e, blocking gustatory chemoreceptors of the maxillary palps and suppressing ingestion by 60\u0026ndash;90% (Mordue et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2010\u003c/span\u003e); (iii) \u003cem\u003eintestinal cytotoxicity\u003c/em\u003e, inducing apoptosis in columnar cells of the intestinal epithelium with cytoplasmic vacuolization, loss of microvilli, and permeabilization of the peritrophic membrane (Zhang et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); (iv) \u003cem\u003eimmunosuppression and gene regulation\u003c/em\u003e, suppressing phenoloxidase (PO) and negatively regulating CYP6, CYP9, and GSTs (Huang et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e3.6.2. Salannin, Nimbin, Gedunin, and Azadiradione\u003c/h2\u003e \u003cp\u003eSalannin (C₃₄H₄₄O₉) specifically activates deterrent chemoreceptor neurons with nanomolar binding constants, generating immediate rejection without systemic absorption (Senthil-Nathan, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Nimbin (C₃₀H₃₆O₉) exerts immunosuppressive activity on granular hemocytes and plasmatocytes, inhibiting PO and antimicrobial peptide synthesis, and alters peritrophic membrane permeability, facilitating secondary penetration of azadirachtin A into the hemocoel in L3\u0026ndash;L5 larvae (Schmutterer, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; Machekano et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Gedunin (C₂₈H₃₄O₇) competitively inhibits Hsp90 of \u003cem\u003eS. frugiperda\u003c/em\u003e, causing ubiquitin-proteasome degradation of the EcR complex and amplifying molting disruption in L3\u0026ndash;L5 (Kumar et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Azadiradione (C₂₈H₃₄O₄, log P\u0026thinsp;\u0026asymp;\u0026thinsp;4.2) acts as a contact insecticide on the epicuticular membrane and exhibits antibacterial activity against the intestinal microbiome (Schmutterer, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; Campos et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section3\"\u003e \u003ch2\u003e3.6.3. Flavonoids and Fatty Acids: Enzymatic Synergy and Vehicular Function\u003c/h2\u003e \u003cp\u003eQuercetin (C₁₅H₁₀O₇) competitively inhibits CYP6 and CYP9 monooxygenases (phase I) and GSTs (phase II), prolonging the systemic half-life of azadirachtin by 15\u0026ndash;30% (Huang et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); at concentrations\u0026thinsp;\u0026gt;\u0026thinsp;100 \u0026micro;M it acts as a pro-oxidant in hemocytes, activating caspase-3/9 apoptotic pathways (Simmonds, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). Kaempferol (C₁₅H₁₀O₆) co-inhibits CYP P450 and maintains antifungal activity and synergy with azadirachtin in L2\u0026ndash;L4 (Senthil-Nathan, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Catechin and epicatechin (C₁₅H₁₄O₆, trans and cis configurations, respectively) inhibit phase I and II detoxification enzymes, incapacitating the insect from neutralizing the toxic complex (Riaz et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Oleic acid (C₁₈H₃₄O₂, 50\u0026ndash;60% of the oil), through its Δ⁹-cis geometry, improves the cuticular penetration of azadirachtin by interacting with epicuticular lipids. Linoleic acid (C₁₈H₃₂O₂, 15\u0026ndash;20%) acts as a co-vehicle and can generate lipid hydroperoxides (LOOHs) under UV radiation, contributing to cuticular oxidative stress (Campos et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e3.7. Chronic Impact and Suppression of Reproductive Dynamics\u003c/h2\u003e \u003cp\u003eThe impact of neem formulations on \u003cem\u003eS. frugiperda\u003c/em\u003e transcends the lethal control of immature stages. Endocrine disruption significantly reduces juvenile hormone (JH) titers in females, blocking vitellogenin synthesis in the fat body, causing severe ovarian atrophy and subclinical sterility (Medina et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Transfer of limonoid residues to egg chorion prevents embryogenesis (trans-ovarian ovicidal effect), while in exposed males a drastic reduction in sperm motility is documented (S\u0026aacute;enz-de-Cabez\u0026oacute;n et al., \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). The high sensitivity of gravid females to polyphenols present on treated leaf surfaces triggers an oviposition deterrence response mediated by tarsal and ovipositor receptors (Viana \u0026amp; Prates, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). This set of chronic effects strengthens the role of neem as an integral tool in IPM of \u003cem\u003eS. frugiperda\u003c/em\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e3.8. Influence of Altitude and High-Altitude Climatic Conditions\u003c/h2\u003e \u003cp\u003eIn Andean agroecosystems such as those of Pamplona, Norte de Santander (2,586 m a.s.l., 17\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026deg;C), climatic variables substantially modify the stability of extracts and the ecophysiology of \u003cem\u003eS. frugiperda\u003c/em\u003e. At higher altitude, the reduced atmospheric filtration increases the incidence of ultraviolet radiation, accelerating the photooxidation of photolabile limonoids and reducing their half-life on the foliar canopy (Barrek et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Isman, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). The works of Giraldo-Vanegas et al. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2026a\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003eb\u003c/span\u003e) under these conditions employed 5\u0026ndash;7-day application intervals, evidencing the technical necessity of microemulsions or UV-protective adjuvants. The emerging nanoformulations reported by Wu et al. (\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) and Bezerra et al. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), which extend azadirachtin half-life to 7\u0026ndash;21 days, represent particularly promising solutions for high-altitude Andean conditions.\u003c/p\u003e \u003cp\u003eFrom a thermodynamic standpoint, the high-altitude mountain climate reduces the basal metabolic rate of poikilotherm insects. In \u003cem\u003eS. frugiperda\u003c/em\u003e, this prolongs the duration of each larval stadium (Garc\u0026iacute;a-Roa et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; N\u0026uacute;\u0026ntilde;ez-Garc\u0026iacute;a et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), extending the exposure window to the biopesticide, while also decreasing the foliar consumption rate and ingestion of active principles (Smirle et al., \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e1996\u003c/span\u003e). Nevertheless, low temperatures also depress the enzymatic efficiency of GST and oxidases in the insect, shifting the locus of control from acute mortality toward sustained endocrine disruption that collapses molting and sterilizes adult populations. The LT₅₀ values documented by Giraldo-Vanegas et al. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2026b\u003c/span\u003e) \u0026mdash; up to 196.69 h in L5 at 17\u0026deg;C \u0026mdash; reflect this particular temporal dynamics of neem biological activity under Andean conditions.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Conclusions","content":"\u003cp\u003eThe bibliographic review synthesized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e (28 studies, 1990\u0026ndash;2026) and the analysis of the phytochemical profile of \u003cem\u003eA. indica\u003c/em\u003e A. Jussieu (Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) allow the following conclusions on the use of its formulations against \u003cem\u003eS. frugiperda\u003c/em\u003e (J. E. Smith).\u003c/p\u003e \u003cp\u003eFormulations of \u003cem\u003eA. indica\u003c/em\u003e \u0026mdash; especially EC oil and NSKE \u0026mdash; exert significant insecticidal and antifeedant activity on \u003cem\u003eS. frugiperda\u003c/em\u003e, with differential susceptibility favoring control of L1\u0026ndash;L3 instars (LC₅₀ = 580\u0026ndash;703 \u0026micro;L/L; LT₅₀ = 21\u0026ndash;67 h) compared with L4\u0026ndash;L6 (LC₅₀ = 795\u0026ndash;921 \u0026micro;L/L; LT₅₀ = 90\u0026ndash;410 h). The critical physiological threshold between L3 and L4 is associated with cuticle thickening, increased CYP6/CYP9 expression, and toxicokinetic dilution documented by Wang et al. (\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) and Giraldo-Vanegas et al. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2026a\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003eb\u003c/span\u003e). This threshold determines the optimal application window for maximum efficacy.\u003c/p\u003e \u003cp\u003eThe multi-target mechanisms of action of \u003cem\u003eA. indica\u003c/em\u003e metabolites \u0026mdash; ecdysteroid antagonism, gustatory inhibition, intestinal cytotoxicity, immunosuppression, and enzymatic inhibition of detoxification systems \u0026mdash; constitute a strategy that saturates the phenotypic plasticity of \u003cem\u003eS. frugiperda\u003c/em\u003e, delaying the selection of resistant biotypes and consolidating neem as a cornerstone for IPM sustainability across different altitudinal zones. This multicomponent synergistic action explains the greater efficacy of crude \u003cem\u003eA. indica\u003c/em\u003e oil over purified azadirachtin.\u003c/p\u003e \u003cp\u003eIn field conditions, efficacy ranges between 40% and 85% damage reduction in \u003cem\u003eZ. mays\u003c/em\u003e crops, conditioned primarily by the larval instar at the time of application, the environmental stability of the formulation, and the use of adjuvants. Emerging nanoformulations \u0026mdash; microencapsulation, chitosan nanocomposites \u0026mdash; represent a technological priority for overcoming the photolability limitation of conventional EC formulations, with demonstrated improvements in half-life and efficacy in both laboratory and semi-field conditions.\u003c/p\u003e \u003cp\u003eKey knowledge gaps identified include: (i) scarcity of field studies in high-altitude Andean ecosystems with \u003cem\u003eS. frugiperda\u003c/em\u003e; (ii) insufficient field evidence for emerging formulations (nanotechnology, microencapsulation); (iii) absence of complete molecular characterization of the ontogenetic resistance of \u003cem\u003eS. frugiperda\u003c/em\u003e to neem oil through comparative transcriptomics across all six larval instars; and (iv) the need for studies integrating the effect of the complete phytochemical complex of neem \u0026mdash; including margolones, catechins, and amide alkaloids \u0026mdash; on pest population dynamics in the field.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eHGV: conceptualization, investigation, writing and editing. GGH: critical review, data analysis, and methodology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work received no specific external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eThe data supporting the findings of this study are available upon reasonable request from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAlmeida, C. (2021). \u003cem\u003eEficacia del neem y aceite vegetal para el control de Spodoptera frugiperda en el cultivo de ma\u0026iacute;z (Zea mays)\u003c/em\u003e [Master\u0026apos;s thesis, Universidad Agraria del Ecuador].\u003c/li\u003e\n\u003cli\u003eBarrek, S., Paisse, O., \u0026amp; Grenier-Loustalot, M. F. (2004). 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Transcriptome analysis reveals immune-related genes and pathways in \u003cem\u003eSpodoptera frugiperda\u003c/em\u003e midgut after oral infection with \u003cem\u003eBacillus thuringiensis\u003c/em\u003e. \u003cem\u003eFrontiers in Microbiology\u003c/em\u003e, 14, 1156304. https://doi.org/10.3389/fmicb.2023.1156304\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Spodoptera frugiperda, Azadirachta indica, botanical insecticides, biopesticides, phytochemistry, integrated pest management, Andean agroecosystems, nanoformulations","lastPublishedDoi":"10.21203/rs.3.rs-9361769/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9361769/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe fall armyworm, \u003cem\u003eSpodoptera frugiperda\u003c/em\u003e (J. E. Smith) (Lepidoptera: Noctuidae), is one of the most economically damaging cereal pests globally, with yield losses exceeding 30%. The neem tree, \u003cem\u003eAzadirachta indica\u003c/em\u003e A. Jussieu (Meliaceae), contains over 200 bioactive secondary metabolites, with azadirachtin A (C₃₅H₄₄O₁₆) as the most potent insecticidal compound. This review systematizes scientific evidence published between 2015 and 2026 on the use of oil, aqueous extracts, and formulations of \u003cem\u003eA. indica\u003c/em\u003e against \u003cem\u003eS. frugiperda\u003c/em\u003e under laboratory and field conditions, analyzing formulation efficacy, multi-target mechanisms of action, and the influence of high-altitude climatic conditions on biopesticide performance. Formulated neem oil at 500\u0026ndash;1,500 \u0026micro;L/L achieves larval mortality exceeding 70% in early instars (L1\u0026ndash;L3), with LC₅₀ = 580\u0026ndash;703 \u0026micro;L/L and LT₅₀ = 21\u0026ndash;67 h. Metabolite modes of action include ecdysteroid antagonism, gustatory inhibition, intestinal cytotoxicity, immunosuppression, and enzymatic inhibition of detoxification systems (Tables\u0026nbsp;1 and 3), constituting a multi-target strategy that minimizes resistance development risk in \u003cem\u003eS. frugiperda\u003c/em\u003e. Emerging nanoformulations (microencapsulation, chitosan-azadirachtin nanoparticles) show LC₅₀ values up to 2.5-fold lower and extended environmental half-lives of 7\u0026ndash;21 days compared with conventional emulsifiable concentrates, constituting a priority area for future research and commercial development.\u003c/p\u003e","manuscriptTitle":"Use of Oil, Aqueous Extracts, and Formulations of Azadirachta indica A. Jussieu against Spodoptera frugiperda: A Systematic Review (2015–2026)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-10 07:29:25","doi":"10.21203/rs.3.rs-9361769/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"99621bfd-a944-49a4-8ab6-67b96e24cfda","owner":[],"postedDate":"April 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":65974737,"name":"Agronomy"},{"id":65974738,"name":"Agroecology"}],"tags":[],"updatedAt":"2026-04-10T07:29:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-10 07:29:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9361769","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9361769","identity":"rs-9361769","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}