Induction and sustainable production of cannabinoids in Cannabis sativa L. callus cultures using Yarrowia lipolytica biogenic silver nanoparticles

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Researchers have demonstrated a novel way to stimulate THC and CBD production in cannabis tissue using biologically produced silver nanoparticles. In untreated Cannabis sativa callus cultures, THC and CBD were undetectable. But after treatment with biogenic silver nanoparticles produced using the yeast Yarrowia lipolytica, the cultures accumulated 0.31% THC and 0.26% CBD while also increasing expression of the THCAS and CBDAS genes involved in cannabinoid biosynthesis.

The findings demonstrate that cannabinoid production can be induced in undifferentiated cannabis tissue that lacks the specialized glandular trichomes normally associated with cannabinoid production. Researchers say the technique could contribute to climate-independent, sustainable production systems for cannabinoids and other medicinal plant compounds.

“Cannabis sativa L. produces cannabinoids as high-value secondary metabolites within the specialized glandular trichomes of mature inflorescences. Large-scale cannabinoid production in conventional agriculture is limited due to extensive land requirements, irrigation requirements, pests and diseases, and reliance on agrochemicals. In vitro platforms offer a reliable and climate-independent alternative for the production of plant-derived compounds. However, cannabinoid biosynthesis in undifferentiated callus tissues remains poorly understood because these tissues lack specialized morphological structures. This study presents an innovative strategy to induce and sustainable production of cannabinoids in C. sativa callus cultures using biogenic silver nanoparticles (AgNPs) synthesized via Yarrowia lipolytica.

Result

After treatment of C. sativa L. callus cultures with biogenic AgNPs, cannabinoids (THC and CBD) were quantified by HPLC and the expression of key biosynthetic genes (CBDAS and THCAS) was analyzed by qPCR. In the control samples, cannabinoids were not detectable. Treatment with 20 mg/L AgNPs led to accumulation of THC (0.31%) and CBD (0.26%). Results of qPCR confirmed upregulation of the biosynthetic genes CBDAS and THCAS. These green AgNPs acted as potent signaling triggers and induce a significant metabolic shift in the callus cultures.

Conclusion

This is the first report demonstrating the effectiveness of biogenic AgNPs in inducing cannabinoid biosynthesis in C. sativa L. callus cultures. These findings highlight a sustainable and eco-friendly approach for the industrial production of plant-derived medicinal compounds.”

https://link.springer.com/article/10.1186/s12896-026-01218-x

Cannabis Medicine 2.0: Nanotechnology-Based Delivery Systems for Synthetic and Chemically Modified Cannabinoids for Enhanced Therapeutic Performance

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Cannabinoid medicine is increasingly moving beyond conventional oils, capsules and extracts toward advanced drug-delivery technologies designed to improve how these compounds reach their targets in the body. This 2025 review examines how nanotechnology-based delivery systems may improve the solubility, stability, bioavailability and targeted delivery of synthetic and chemically modified cannabinoids.

Researchers reviewed nanoparticles, lipid-based carriers, micelles, nanoemulsions and other nanoengineered systems being developed for cannabinoid-related therapies. These technologies have been investigated in preclinical research involving conditions including neuropathic pain, depression and cancer, with some formulations producing longer-lasting or more targeted effects while reducing systemic exposure.

The authors conclude that combining cannabinoid pharmacology with nanotechnology could help create a new generation of more precise cannabinoid medicines, although most of these approaches remain in the preclinical stage and will require additional testing and regulatory development before widespread clinical use.

“The therapeutic potential of cannabinoids and other ligands of cannabinoid receptors attracts considerable attention due to their diverse pharmacological effects and utility in various medical applications. However, challenges such as low solubility, limited bioavailability, and potential side effects hinder their broad clinical use. Nanoformulation techniques offer a promising approach to address these issues and optimize the therapeutic effectiveness of cannabinoids and other cannabinoid receptor ligands.

This comprehensive review explores the advancements in nanoformulation strategies to enhance the therapeutic efficacy and safety of synthetic cannabinoids and related compounds, such as CB13, rimonabant, and HU-211, which have been studied in a range of preclinical models addressing conditions such as neuropathic pain, depression, and cancer.

The review discusses various nanocarriers employed in this field, including lipid-based, polymeric, and hybrid nanoparticles, micelles, emulsions, and other nanoengineered carriers. In addition to formulation approaches, this review provides an in-depth analysis of chemical structures and their effect on compound activity, especially in the context of the affinity for the cannabinoid type 1 receptor in the brain, which is chiefly responsible for the psychoactive effects.

The provided summary of research concerning either chemical modifications of existing cannabinoids or the creation of new compounds that interact with cannabinoid receptors, followed by the development of nanoformulations for these agents, allows for the identification of new research directions and future perspectives for Cannabis-based medicine.

In conclusion, the combination of nanotechnology and cannabinoid pharmacology holds promise for delivering more effective and safer therapeutic solutions for a broad spectrum of medical conditions, making this an exciting area of research with profound implications for the healthcare and pharmaceutical industries.”

“Nanotechnology-enabled delivery of synthetic and chemically modified cannabinoids offers a promising approach to overcome the intrinsic limitations of these compounds, positioning them as candidates for future precision therapeutics. Preclinical evidence supports their enhanced stability, bioavailability, and site-specific activity; however, translating these findings into clinical applications will require coordinated advances in innovation, manufacturing, and regulatory science. Nanoformulated cannabinoids have the potential to transform therapeutic strategies, but their clinical impact will depend on harmonized regulations, standardized testing, and robust translational research. With sustained international collaboration, these next-generation formulations may become a key component of personalized medicine in the coming decade.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC12388155/

Green synthesis of cannabinoids loaded gold nanoparticles displaying enhanced anti-cancer properties

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Researchers developed gold nanoparticles capable of carrying the highly hydrophobic cannabinoids THC and CBD into cancer cells, increasing their bioavailability and anti-cancer activity. The nanoparticles acted as a scaffold for cannabinoid attachment and enhanced transport inside cancer cells. Compared with aqueous suspensions of the pure cannabinoids, the nanoparticle-loaded THC and CBD produced cancer cell death more efficiently, supporting gold nanoparticles as a potential delivery system for cannabinoid-based cancer treatment.

“This study investigates the anti-cancer potential of cannabinoids loaded onto gold nanoparticles (AuNPs) for targeted cancer treatment. We adopted a multifaceted approach to explore and design this nano system, encompassing its synthesis, physicochemical characterization, stability assessment, and evaluation of anticancer efficacy in 2D and 3D in vitro models.

In this research, we have demonstrated that two highly hydrophobic phytocannabinoids like delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), can be loaded on the surface of AuNPs with a one-pot synthesis protocol using trisodium citrate and l-tyrosine as a reducing and stabilizing agents. l-tyrosine plays a crucial role in cannabinoid loading, stability, and shelf life of the AuNPs.

After synthesis, the cannabinoid-loaded nanoparticles were characterized with UV–vis spectroscopy, dynamic light scattering (DLS), dark field hyperspectral microscopy, and electron microscopy. The AuNPs function as a scaffold for the attachment and enhanced transport of both cannabinoids inside cancer cells, thus increasing their bioavailability. Hyperspectral microscopy was used to confirm AuNPs uptake. IC50 values in SK-BR-3 human breast cancer cell line for both THC and CBD loaded onto AuNPs were lower by 70.75 % and 37.04 % than those of the aqueous suspension of pure molecules.

Compared to the aqueous suspension of pure cannabinoids, this approach induced and enhanced cancer cell death more efficiently. This enhanced efficacy was associated with a decline in cell viability, which is attributed to apoptosis, as indicated by flow cytometry results.

Our findings offer a significant step towards the green design and utilization of AuNPs to deliver cannabinoids into cells efficiently.”

“Cannabinoids loaded on AuNPs were synthesized as a nano-therapeutic drug agent for cancer. This study indicates that AuNPs can be used as efficient carriers for highly hydrophobic molecules with an anti-cancer effect. This protocol was straightforward and effective in entrapment of CBD or THC on the surface of AuNPs. The results revealed reasonable anti-cancer efficacy of this nanosystem in 2D and 3D in vitro cytotoxicity.”

https://www.sciencedirect.com/science/article/pii/S258923472500082X

Nanotechnology for the Efficacious Delivery of Medicinal Cannabis and Pharmaceutical Medicines

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Nanotechnology is creating new possibilities for the delivery of medicinal cannabis and pharmaceutical medicines. This 2025 narrative review examines how nanoscale delivery systems may help overcome common problems such as poor solubility, inconsistent absorption, low bioavailability, gastrointestinal degradation, and first-pass metabolism.

These challenges are especially relevant to cannabinoids such as THC and CBD because they are highly lipophilic compounds. The review discusses how nanoparticle systems may improve cannabinoid stability, targeting, controlled release, selectivity, and overall delivery while exploring alternative routes including oro-buccal, nasal, ocular, and transdermal administration.

The paper directly discusses THC, CBD, dronabinol, nabilone, nabiximols, high-THC cannabis, and NanoCelle™ formulations designed to deliver THC and CBD through the oral mucosa. The authors emphasize that nanotechnology may allow cannabinoid medicines to be delivered more precisely, with improved absorption and reduced loss through first-pass metabolism.

“The application of nanoparticles as nanomedicines, particularly for the targeted and efficacious delivery of drugs is an expanding platform in the field of cannabinoid and pharmaceutical drug delivery. By refocusing the route of drug administration beyond the oral gut pathway, this technology provides significant advancements that are especially relevant for cancer treatments. Orally administered drugs face significant challenges as they traverse the gastrointestinal tract (GIT) and are subject to first-pass GIT metabolism. Physiological conditions encountered in the GIT such as food effects, hormones, gastric pH, emptying time, and intestinal transit time vary widely across individuals. Fluid composition and enzymatic activity in the small intestine and large bowel also influence drug dissolution and absorption. These factors in conjunction with the intestinal cohort of bacteria can metabolize drugs before absorption, contributing to poor and variable drug bioavailability, which can be exacerbated by gut dysbiosis. Drug delivery that bypasses the oral-GIT route and hence first-pass metabolism offers a plausible solution for enhanced safety and drug efficacy.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC12472836

Green synthesis of gold and silver nanoparticles from Cannabis sativa (industrial hemp) and their capacity for biofilm inhibition

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Researchers used Cannabis sativa (industrial hemp) extracts to produce gold and silver nanoparticles through a rapid, economical “green synthesis” process. Hemp contains biologically active compounds including cannabinoids, terpenes, flavonoids, and phenolic compounds, some of which may help form and stabilize nanoparticles.

The hemp-derived silver nanoparticles showed antibacterial and anti-biofilm activity against Pseudomonas aeruginosa and Escherichia coli, including inhibition of biofilm formation at concentrations below those needed to completely stop bacterial growth.

The authors concluded that C. sativa extracts can be effectively used for green nanoparticle synthesis and that some of these nanoparticles may have value against biofilm formation. They also emphasized that “the therapeutic value of this plant is not negligible.”

“Cannabis sativa (hemp) is a source of various biologically active compounds, for instance, cannabinoids, terpenes and phenolic compounds, which exhibit antibacterial, antifungal, anti-inflammatory and anticancer properties. With the purpose of expanding the auxiliary application of C. sativa in the field of bio-nanotechnology, we explored the plant for green and efficient synthesis of gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs).

The nanoparticles were synthesized by utilizing an aqueous extract of C. sativa stem separated into two different fractions (cortex and core [xylem part]) without any additional reducing, stabilizing and capping agents. In the synthesis of AuNPs using the cortex enriched in bast fibers, fiber-AuNPs (F-AuNPs) were achieved. When using the core part of the stem, which is enriched with phenolic compounds such as alkaloids and cannabinoids, core-AuNPs (C-AuNPs) and core-AgNPs (C-AgNPs) were formed. Synthesized nanoparticles were character-ized by UV–visible analysis, transmission electron microscopy, atomic force microscopy, dynamic light scattering, Fourier transform infrared, and matrix-assisted laser desorption/ionization time-of-flight. In addition, the stable nature of nanoparticles has been shown by thermogravimetric analysis and inductively coupled plasma mass spectrometry (ICP-MS). Finally, the AgNPs were explored for the inhibition of Pseudomonas aeruginosa and Escherichia coli biofilms.

Conclusion

The synthesized nanoparticles were crystalline with an average diameter between 12 and 18 nm for F-AuNPs and C-AuNPs and in the range of 20–40 nm for C-AgNPs. ICP-MS analysis revealed concentrations of synthesized nanoparticles as 0.7, 4.5 and 3.6 mg/mL for F-AuNPs, C-AuNPs and C-AgNPs, respectively. Fourier transform infrared spectroscopy revealed the presence of flavonoids, cannabinoids, terpenes and phenols on the nanoparticle surface, which could be responsible for reducing the salts to nanoparticles and further stabilizing them. In addition, the stable nature of synthesized nanoparticles has been shown by thermogravimetric analysis and ICP-MS. Finally, the AgNPs were explored for the inhibition of P. aeruginosa and E. coli biofilms. The nanoparticles exhibited minimum inhibitory concentration values of 6.25 and 5 µg/mL and minimum bactericidal concentration values of 12.5 and 25 µg/mL against P. aeruginosa and E. coli, respectively.”

“This study demonstrated the applicability of C. sativa extracts for rapid and economical green synthesis of nanoparticles, some of which can be effectively used against biofilm formations.

The developed methodology allowed to produce several types of nanoparticles: F-AuNPs, at 1:1 ratio of plant extract:water, 100°C, 4 mM gold salt in 3 min; C-AuNPs, at 1:1 ratio of plant extract:water, 90°C, 2 mM salt in 2.5 min; C-AgNPs, with complete extract, 90°C, 5 mM silver salt in 8 min. C-AgNPs were applied for effective inhibition and disruption of P. aeruginosa and E. coli biofilms. The question generating nanoparticles that would possess the desired morphology with well-defined size and shape is still open, and further study is required to develop a technology in which nanoparticles of specific size and shape can be obtained by the use of medicinal and industrially important C. sativa plants.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC6016601

Exploring the Potential of Cannabinoid Nanodelivery Systems for CNS Disorders

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Cannabinoids such as THC and CBD have shown therapeutic potential in neurological disorders, but poor water solubility and low bioavailability can limit their effectiveness. This review explores how nanotechnology may overcome these barriers by improving cannabinoid stability, controlled release and targeted delivery to the central nervous system, including strategies designed to enhance passage across the blood-brain barrier.

“Cannabinoids have a major therapeutic value in a variety of disorders. The concepts of cannabinoids are difficult to develop, but they can be used and are advantageous for a number of diseases that are not sufficiently managed by existing treatments. Nanoconjugation and encapsulation techniques have been shown to be effective in improving the delivery and the therapeutic effectiveness of drugs that are poorly soluble in water. Because the bioavailability of cannabinoids is low, the challenge is to explore different administration methods to improve their effectiveness. Because cannabinoids cross the blood-brain-barrier (BBB), they modify the negative effects of inflammatory processes on the BBB and may be a key factor in the improvement of BBB function after ischemic disease or other conditions. This review discusses various types of cannabinoid administration, as well as nanotechnologies used to improve the bioavailability of these compounds in CNS diseases.”

“The growing acceptance of Cannabis and cannabinoids has led to an increasing number of clinical trials testing various nanoproducts. CNS disorders are key therapeutic targets for cannabinoids, and nanoformulation platforms for cannabinoid nanoconjugates provide efficient transport across the BBB. Selected examples of cannabinoid nanoconjugates have shown enhanced bioavailability and improved bio-efficacy with promising outcomes in biomedical applications. We expect to see many results from clinical trials in the near future to evaluate the adverse effects and effectiveness of this treatment. However, precise delivery of these nanoformulations to pathological sites inside the brain remains a challenge.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC9863859/

Mucus-Penetrating Nanostructured Lipid Carriers: An Effective Approach for Cannabidiol to Pass Across the Nasal Mucus-Mucosal Barrier

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Researchers developed nanostructured lipid carriers designed to help cannabidiol (CBD) penetrate the nasal mucus and cross nasal epithelial cells, potentially improving nose-to-brain drug delivery. In laboratory experiments using rat nasal mucosal epithelial cells, the carriers showed little interaction with mucin, promoted mucus penetration, were efficiently taken up by cells, and improved CBD transport across the cell layer. The findings support mucus-penetrating lipid nanoparticles as a promising delivery platform for getting CBD across the nasal mucus-mucosal barrier and potentially toward the brain.

“Effective nose-to-brain delivery is limited by the mucus-mucosal barrier, which severely hinders drug transport after nasal administration. Although nanostructured lipid carriers (NLCs) offer promising solutions by improving their retention duration in the mucosal layer or promoting mucosal permeation and intracellular uptake, the nanoparticle-mucus interactions, epithelial uptake, and mechanisms supporting transcellular transport in the nasal cavity remain poorly learned.

This study was developed to assess the interactions between mucin and NLCs, the absorption and transport capabilities of Cannabidiol (CBD) nanostructured lipid carriers (CBD-NLCs) in rat nasal mucosal epithelial (RNME) cells.

Molecular docking (MD) was used to evaluate the interactions between the human mucin protein MUC5AC (hMUC5AC) and some main components of CBD-NLCs. In vitro experiments were conducted to assess the mucus penetration of CBD-NLCs. Cellular uptake, localization, and transport mechanisms of coumarin-6-labeled NLCs (C6-NLCs) in RNME cells were examined by confocal laser scanning microscopy, endocytosis inhibition assays, and transcellular transport assays.

Our results show that there were no interactions between the main components of NLCs and hMUC5AC according to MD simulations. In vitro experiments, NLCs promoted mucus penetration and had little interaction with mucin. Cellular studies confirmed cytoplasmic (non-nuclear) localization of C6-NLCs in RNME cells, and transport assays showed that the clathrin-mediated endocytic route was a predominant pathway for their internalization. When across the RNME cell monolayer, NLCs had a great benefit on CBD transportation across monolayers of RNME cells.

Our results clarify the mechanism by which NLCs enhance mucosal penetration and facilitate cellular trafficking in RNME cells. Their little interaction with mucin, combined with efficient cellular uptake and transcellular transport, supports the potential of NLCs as a promising nanoplatform for nose-to-brain drug delivery.”

https://pubmed.ncbi.nlm.nih.gov/42698223/

https://onlinelibrary.wiley.com/doi/10.1002/jbm.a.70133

Endocannabinoid system dysregulation in non-communicable diseases: Implications for skeletal muscle health

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Researchers reviewing the endocannabinoid system across non-communicable diseases found that ECS dysregulation is common in multiple disease states and may contribute to associated skeletal muscle wasting. Preclinical evidence suggests that modulating endocannabinoid signaling could improve both disease-related symptoms and muscle degeneration, highlighting the ECS as a potentially important therapeutic target across chronic disease.

“Non-communicable diseases (NCDs) and their associated skeletal muscle (SkM) degeneration substantially contribute to morbidity and mortality. Interestingly, the endocannabinoid system (ECS) is increasingly recognized as an important regulator of both NCD pathophysiology and SkM plasticity.

This narrative review summarizes the interplay between the ECS, NCDs and SkM degeneration – a potentially interesting triad that has not yet been comprehensively described, but may stimulate future research into the role of ECS-targeted interventions in the context of disease-associated SkM wasting. Therefore, we performed a narrative synthesis of (pre)clinical studies, focusing on alterations in ECS components (endocannabinoids, enzymes, receptors), the effects of ECS modulation (e.g. receptor (ant)agonism or enzyme inhibition), and SkM degeneration symptoms, across various (models of) NCDs. Additionally, the current literature on ECS modulation and SkM degeneration in non-disease models was summarized.

The main findings show that ECS composition is consistently altered in different NCDs, including obesity, cancer (cachexia), liver disease, kidney disease, cardiovascular disease and inflammatory bowel disease. Pharmacological or genetic ECS modulation has been reported to improve several disease-related outcomes, e.g. insulin resistance, liver fibrosis and renal inflammation, predominantly in preclinical models.

These NCDs also exhibit hallmarks of SkM degeneration, including atrophy, impaired regeneration, inflammation, and weakness. Notably, ECS modulation could ameliorate SkM pathology in various preclinical myopathy models, raising the hypothesis of an ECS-disease-muscle axis. However, this hypothesis requires further validation, as studies directly evaluating ECS-based interventions in disease-associated SkM degeneration remain limited.

Future research should directly evaluate the existence of this potential ECS-disease-muscle axis by generating more (human) data on ECS modulation in the context of disease-associated muscle wasting.”

https://pubmed.ncbi.nlm.nih.gov/42697445

“The endocannabinoid system (ECS) is dysregulated in different internal diseases.”

“The endocannabinoid system might be involved in disease-associated muscle wasting.”

“ECS modulation could improve preclinical symptoms of skeletal muscle degeneration.”

https://www.sciencedirect.com/science/article/pii/S0531556526002913?via%3Dihub

Prospects in the Use of Cannabis sativa Extracts in Nanoemulsions

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Cannabis sativa contains a wide range of biologically active compounds with medicinal potential, including cannabinoids, terpenes, flavonoids and other plant chemicals. This review examined extraction methods and nanoemulsion technologies that could improve the stability, delivery, bioavailability and preservation of these compounds while expanding the potential use of whole-plant cannabis extracts.

The authors highlight antioxidant, antimicrobial and immunomodulatory activity associated with Cannabis sativa extracts and argue that nanoformulations could help move this research toward broader pharmaceutical development. They specifically call for greater industry participation to advance new delivery methods, scale up cannabis nanoemulsion production and support the progression from animal research toward eventual human applications.

“Cannabis sativa plants have been widely investigated for their specific compounds with medicinal properties. These bioactive compounds exert preventive and curative effects on non-communicable and infectious diseases.

However, C. sativa extracts have barely been investigated, although they constitute an affordable option to treat human diseases.

Nonetheless, antioxidant, antimicrobial, and immunogenicity effects have been associated with C. sativa extracts.

Furthermore, innovative extraction methods in combination with nanoformulations have been proposed to increase desirable compounds’ availability, distribution, and conservation, which can be aided by modern computational tools in a transdisciplinary approach.

This review aims to describe available extraction and nanoformulation methods for C. sativa, as well as its known antioxidant, antimicrobial, and immunogenic activities. Critical points on the use of C. sativa extracts in nanoformulations are identified and some prospects are envisaged.”

https://pubmed.ncbi.nlm.nih.gov/39727490

“Given all this, the pharmaceutical industry’s active participation is needed to advance and exploit other forms of distribution in animals and, finally, application in humans.”

“The industry could participate in innovation in harnessing Cannabis and scaling up the production of nanoemulsions.” 

https://www.mdpi.com/2673-6284/13/4/53


Analgesic effect of delta-9-tetrahydrocannabinol

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A preliminary double-blind clinical trial found that oral delta-9-tetrahydrocannabinol (THC) produced significant pain relief in patients with cancer pain. In the 10-patient study, THC doses of 15 and 20 mg provided significantly greater analgesic effects than placebo.

The study’s main clinical takeaway is that THC showed a measurable analgesic effect at higher oral doses, but the benefit was accompanied by dose-limiting central nervous system side effects. In practical terms, the findings suggest a potential role for THC in cancer pain management while also underscoring the importance of balancing pain relief against sedation, cognitive impairment, and overall tolerability.

“A preliminary trial of oral delta-9-tetrahydrocannabinol (THC) demonstrated an analgesic effect of the drug in patients experiencing cancer pain. Placebo and 5, 10, 15, and 20 mg THC were administered double blind to ten patients. Pain relief significantly superior to placebo was demonstrated at high dose levels (15 and 20 mg). At these levels, substantial sedation and mental clouding were reported.”

https://pubmed.ncbi.nlm.nih.gov/1091664

https://accp1.onlinelibrary.wiley.com/doi/10.1002/j.1552-4604.1975.tb02348.x

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