A Review on Neem Nanoparticles used in Cancer Therapy
Vaishnavi Ashok Gore
Swastyadarpan Pratishthan’s, Shantiniketan College of Pharmacy,
A/P Dhotre (B.K.), Tal. Parner, Ahmednagar, Maharashtra – 414302.
*Corresponding Author E-mail: vaishnavigore04042004@gmail.com
Abstract:
In 2024, India was estimated to have 1.56 million new cancer cases and 874,404 cancer deaths, according to a study by the Indian Council of Medical Research (ICMR). In recent years, nanoparticles have drawn a lot of interest as a promising drug delivery system to address this challenge, particularly for the treatment of cancer. Nanoparticles, or particles with a size of roughly 10 to 100 nanometers, have the potential to be especially effective agents in the detection, diagnosis, and treatment of cancer because of their size and supramolecular structures. The study describes how different nanoparticles—such as liposomes, polymeric nanoparticles, dendrimers, and magnetic nanoparticles—are used for targeted drug delivery. When compared to conventional therapy, these nanoparticledrug formulations can improve the safety, pharmacokinetic profiles, and bioavailability of the administered drugs, resulting in increased therapeutic efficacy. Nanomedicine products represent an opportunity to achieve sophisticated targeting Strategies and multifunctionality. Azadirachta indica (neem), a medicinal plant with a well-documented history in Ayurvedic medicine, is a rich source of bioactive limonoids possessing potent anticancer properties. This review comprehensively examines the convergence of neem phytochemistry and nanotechnology, focusing on the green synthesis of neem-based nanoparticles (NPs) and their multifaceted mechanisms against cancer. We elaborate on the efficacy of various neem NPs, including silver, gold, zinc oxide, and polymeric NPs, in inducing apoptosis, generating reactive oxygen species (ROS), inhibiting metastasis, and modulating key oncogenic pathways. Discusses the current challenges, and presents future perspectives for the clinical translation of neem nanoparticles as a cornerstone of integrative oncology. This study explores a novel herbal drug delivery system utilizing neem nanoparticles for the targeted delivery of anticancer compounds, enhancing therapeutic efficacy.
KEYWORDS: Nanoparticles, Cancer, Targeted Drug delivery, Liposomes, Neem, NHDDS.
1. INTRODUCTION:
Cancer is one of the most complex and life-threatening diseases worldwide, characterized by uncontrolled cell proliferation, invasion, and metastasis to distant organs. It arises from genetic and epigenetic alterations that disrupt the normal mechanisms regulating cell growth and apoptosis, leading to tumor formation and progression 1. According to the World Health Organization (WHO), cancer remains a leading cause of death globally, accounting for nearly 10 million deaths in 2022 2. Despite remarkable advances in diagnosis and treatment, the global incidence of cancer continues to rise, largely due to 2/11 Population aging, environmental exposure, and lifestyle-related risk factors such as tobacco use, poor diet, and physical inactivity 3,4. The complexity of cancer lies in its heterogeneity both inter- and intra-tumoral which makes it difficult to achieve universal therapeutic success 5. Conventional therapies, including chemotherapy, radiotherapy, and surgery, are often associated with severe side effects, limited selectivity, and the resistance 6 These traditional treatments often lack specificity, resulting in damage to healthy tissues, systemic toxicity, and the emergence of multidrug resistance, which significantly limit their effectiveness6,7. Therefore, there is an urgent need for more selective and efficient therapeutic strategies capable of delivering anticancer agents directly to tumor cells while minimizing adverse effects.
Nanotechnology has emerged as a promising tool in oncology, offering innovative solutions for cancer diagnosis, imaging, and therapy. Nanoparticles (NPs), typically ranging from 10 to 100 nanometers in size, possess unique physicochemical properties such as a high surface-area-to-volume ratio, tunable surface chemistry, and the ability to encapsulate both hydrophilic and hydrophobic drugs8,9. These features enable nanoparticles to improve drug solubility, enhance bioavailability, and achieve controlled or sustained release of anticancer agents10. Furthermore, nanoparticle-based drug delivery systems can be engineered for passive or active targeting. Passive targeting exploits the enhanced permeability and retention (EPR) effect of tumor vasculature, allowing nanoparticles to accumulate preferentially at tumor sites11. Active targeting involves the functionalization of nanoparticle surfaces with ligands such as antibodies, peptides, or folic acid, which specifically bind to overexpressed receptors on cancer cells, thereby improving selectivity and therapeutic efficacy12,13. Various nanoparticle platforms including liposomes, polymeric nanoparticles, dendrimers, metallic nanoparticles, and lipid-based nanocarriers—have been extensively investigated for cancer therapy14,15. Some nanoparticle formulations, such as liposomal doxorubicin and albumin-bound paclitaxel, have already received FDA approval, demonstrating the clinical potential of nanotechnology-based cancer therapeutics16. Azadirachta indica, commonly known as neem, has been extensively studied for its broad-spectrum pharmacological activities, including its remarkable anticancer potential17. Bioactive constituents such as nimbolide, azadirachtin, gedunin, and margolone have been identified as key mediators of these effects, demonstrating abilities to suppress proliferation, induce cell cycle arrest, and promote apoptosis in various cancer models18,19.
Despite this promise, the inherent limitations of phytochemicals—such as poor pharmacokinetic profiles and instability—impede their clinical application20. Nanotechnology has emerged as a transformative tool to overcome these hurdles. Nanoparticles can enhance the solubility, stability, and bioavailability of encapsulated drugs, while the Enhanced Permeability and Retention (EPR) effect allows for passive targeting to tumor tissues21. The "green synthesis" of NPs using neem extracts is particularly advantageous, as it is eco-friendly, cost-effective, and the phytochemicals act as both reducing and capping agents, often imparting synergistic biological activity22. This review aims to consolidate the current scientific knowledge on the synthesis, mechanisms, and anticancer efficacy of neem-derived nanoparticles.
The synthesis of nanoparticles using neem extracts is a single-step, bioreduction process. The polyphenols, flavonoids, terpenoids, and reducing sugars present in the extract reduce metal ions to their zero-valent atomic state, which then nucleate and form stable nanoparticles.
2.1 Neem-Silver Nanoparticles (Neem-AgNPs): These are the most widely investigated. The high reducing power of neem leaf extract facilitates the rapid formation of stable, spherical AgNPs. These nanoparticles have demonstrated potent cytotoxic effects against a wide array of cancer cells23,24.
2.2 Neem-Gold Nanoparticles (Neem-AuNPs): Known for their biocompatibility and surface plasmon resonance properties, Neem-AuNPs are explored for both chemotherapy and photothermal therapy. The neem capping layer provides additional anticancer functionality25,26.
2.3 Neem-Zinc Oxide Nanoparticles (Neem-ZnO NPs): Neem-synthesized ZnO NPs are potent inducters of ROS. Their semiconductor properties, combined with the bioactivity of neem compounds, lead to significant oxidative stress in cancer cells27,28.
2.4 Polymeric Nanoparticles Loaded with Neem Bioactives: To achieve controlled and sustained release, neem compounds like nimbolide have been encapsulated within biodegradable polymers such as PLGA (poly (lactic-co-glycolic acid)) and chitosan. This approach significantly improves pharmacokinetics and therapeutic index29,30.
The anticancer activity of neem nanoparticles is not attributed to a single pathway but rather a orchestration of multiple pro-death mechanisms.
3.1 Induction of Apoptosis: This is a hallmark mechanism. Neem NPs upregulate the expression of pro-apoptotic proteins (e.g., Bax, Bak) and downregulate anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL). This mitochondrial dysfunction leads to the release of cytochrome c and activation of the caspase cascade (caspase-9 and caspase-3), culminating in programmed cell death24,31. For instance, nimbolide-loaded PLGA nanoparticles were shown to significantly enhance caspase-3 activation in pancreatic cancer cells compared to free nimbolide30.
3.2 Generation of Reactive Oxygen Species (ROS): Metal-based neem NPs, particularly AgNPs and ZnO NPs, are potent generators of intracellular ROS. The excessive oxidative stress overwhelms the antioxidant defense mechanisms of cancer cells, causing damage to DNA, proteins, and lipids, thereby triggering apoptosis and autophagy27,32. A study on Neem-AgNPs demonstrated a dose-dependent increase in ROS in MCF-7 breast cancer cells, correlating directly with cell death23.
3.3 Inhibition of Cell Proliferation and Metastasis: Neem bioactives are known to suppress key signaling pathways that drive tumorigenesis. Nimbolide, for example, effectively inhibits the NF-κB pathway, a master regulator of inflammation, proliferation, and metastasis19. Nano-formulations enhance the delivery of these compounds, leading to potent downregulation of matrix metalloproteinases (MMPs) and suppression of epithelialto-mesenchymal transition (EMT), thereby curbing invasion and metastasis33.
3.4. Anti-angiogenic Effects: Tumors require neovascularization for growth and dissemination. Neem extracts have demonstrated anti-angiogenic properties by inhibiting VEGF (Vascular Endothelial Growth Factor) and other pro-angiogenic factors34.
Nanoparticles can target the tumor vasculature, enhancing the local concentration of these inhibitors and effectively "starving" the tumor35.
3.5 Cell Cycle Arrest: Neem nanoparticles can disrupt the cell cycle progression of cancer cells. Studies have shown arrest at various phases, including the G0/G1 and G2/M checkpoints, preventing cells from entering the mitotic phase. This is often mediated by the modulation of cyclins and cyclin-dependent kinases (CDKs)36,37.
In Vitro Studies:
· Breast Cancer: Neem-AgNPs showed selective cytotoxicity against MCF-7 and MDA-MB231 breast cancer cells, with minimal effects on non-tumorigenic MCF-10A cells, indicating a favorable therapeutic window23,38.
· Prostate Cancer: Gedunin-loaded nanoparticles exhibited enhanced growth inhibitory effects on PC-3 and LNCaP prostate cancer cell lines by modulating the AR and HSP90 signaling pathways39.
· Cervical Cancer: Neem leaf extract-mediated AuNPs induced significant apoptosis in HeLa cells through a p53-dependent pathway26.
· Colon Cancer: Neem-ZnO NPs demonstrated potent anti-proliferative effects on HCT116 colon cancer cells, primarily through ROS-mediated DNA damage and apoptosis28.
In Vivo Studies:
· In a murine model of melanoma, topical application of neem extract significantly reduced tumor incidence and volume, an effect that was potentiated by a nano-formulated delivery system40.
· Administration of nimbolide-loaded PLGA nanoparticles in a pancreatic xenograft model resulted in a dramatic reduction in tumor burden and metastasis compared to the free drug, with no signs of overt toxicity30.
· Studies in rat models of hepatocarcinogenesis showed that neem leaf extract protected against cancer development by modulating antioxidant and detoxification enzymes, suggesting a chemopreventive role that could be enhanced with nanotechnology41.
While the preclinical data is compelling,the path to the clinic is fraught with challenges.
· Standardization: The phytochemical composition of neem extract is variable. Establishing standardized extraction and NP synthesis protocols is critical for reproducibility and batchto-batch consistency42.
· Toxicological Profiling: Although "green," the long-term in vivo fate, biodistribution, and potential organ accumulation of these NPs require exhaustive investigation. The line between therapeutic and toxic concentrations of metal NPs must be clearly defined43.
· Scalability and Regulation: Scaling up the GMP-compliant production of wellcharacterized neem NPs is a significant engineering and regulatory hurdle. The complex nature of herbal-nano formulations presents unique challenges for agencies like the FDA44.
6. Future research should be directed towards:
1. Active Targeting: Functionalizing neem NPs with tumor-specific ligands (e.g., folic acid, transferrin, peptides) to achieve active targeting and further reduce off-target effects45.
2. Combination Therapy: Developing co-delivery systems that package neem bioactives with conventional chemotherapeutics to achieve synergistic effects, reverse multidrug resistance, and lower required doses46.
3. Advanced Formulations: Exploring other nano-platforms like liposomes, dendrimers, and exosomes for delivering neem compounds.
4. Robust Clinical Trials: Initiating well-designed Phase I and II clinical trials to establish human safety and efficacy, which is the ultimate step in validating this promising approach.
The integration of the rich pharmacopeia of Azadirachta indica with the precision and enhancement capabilities of nanotechnology represents a frontier in cancer research. Neem nanoparticles successfully address the key limitations of native neem bioactives, offering a platform for improved solubility, stability, and tumor-targeted delivery. Their multifaceted mechanism of action, involving the induction of apoptosis, ROS generation, and inhibition of proliferation and angiogenesis, makes them potent weapons against a spectrum of cancers. Despite the existing challenges, the compelling body of preclinical evidence warrants intensified research efforts. With focused work on standardization, toxicology, and translational development, neem nanoparticles hold immense potential to evolve from a promising experimental therapy into a mainstream clinical modality for cancer _treatment.
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Received on 18.02.2026 Revised on 28.03.2026 Accepted on 30.04.2026 Published on 14.07.2026 Available online on July 25, 2026 Research J. Science and Tech. 2026; 18(3):274-278. DOI: 10.52711/2349-2988.2026.00038
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