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Vol.:(0123456789) AAPS PharmSciTech (2025) 26:137 https://doi.org/10.1208/s12249-025-03145-0 REVIEW ARTICLE Nano‑Engineered Epigallocatechin Gallate (EGCG) Delivery Systems: Overcoming Bioavailability Barriers to Unlock Clinical Potential in Cancer Therapy Mohammad Qutub1 · Ujban Md Hussain2 · Amol Tatode1 · Tanvi Premchandani1 · Rahmuddin Khan3 · Milind Umekar1 · Jayshree Taksande1 · Priyanka Singanwad1 Received: 27 March 2025 / Accepted: 5 May 2025 © The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists 2025 Abstract Epigallocatechin gallate (EGCG), a bioactive polyphenol derived from Camellia sinensis, exhibits multimodal anticancer activity through mechanisms such as apoptosis induction, metastasis suppression, and chemoresistance reversal. Despite its therapeutic promise, clinical application is constrained by rapid metabolism, poor bioavailability, and inconsistent bio- distribution. Recent advances in nanotechnology have enabled the development of innovative delivery systems including pH-responsive nanoparticles, lipid-polymer hybrids, and ligand-functionalized carriers that enhance EGCG stability, tumor targeting, and bioavailability by 3- to fivefold in preclinical models. These platforms also facilitate synergistic co-delivery with chemotherapeutics like doxorubicin, amplifying cytotoxicity and overcoming multidrug resistance. Mechanistically, EGCG modulates oncogenic pathways via NF-κB suppression, caspase activation, and MMP-9 downregulation, demonstrat- ing efficacy across diverse cancer types. However, translational challenges persist, such as nanoparticle toxicity, variable tumor accumulation, and insufficient penetration in hypoxic microenvironments. Regulatory hurdles, including the lack of harmonized global standards for herbal medicinal products, further complicate clinical adoption. To bridge these gaps, future research must prioritize scalable cGMP-compliant manufacturing, rigorous preclinical toxicity profiling, and robust clinical trials to validate safety and efficacy. Addressing these issues could position nanoengineered EGCG as a paradigm-shifting therapy in precision oncology, aligning with ESCOP’s mission to integrate evidence-based phytomedicines into conventional cancer care. This review underscores the necessity of interdisciplinary collaboration to standardize phytopreparations, refine regulatory frameworks, and advance biomarker-driven clinical validation, ultimately unlocking the full potential of EGCG in modern therapeutics. Keywords Epigallocatechin Gallate · Apoptosis · Nanotechnology · Bioavailability · Targeted drug delivery · Combination therapy · Translational oncology Introduction Cancer remains a life-threatening global health crisis, responsible for ~ 10 million deaths in 2020 and projected to cause 13.2 million annual deaths by 2030, imposing immense socioeconomic burdens, with direct medical costs exceeding $200 billion annually in the U.S. alone [1–3]. Conventional treatments such as surgery, chemotherapy, and radiotherapy, while often effective in early stages, are associated with high systemic toxicity, limited efficacy in metastatic or advanced disease, and frequent treatment- related complications[4]. In rectal cancer patients, late radia- tion toxicity includes bowel dysfunction, incontinence, and genitourinary issues, with substantial quality-of-life impacts * Amol Tatode aatatode@gmail.com 1 Department of Pharmaceutics, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India 2 Department of Pharmaceutical Sciences, Rashtrasant Tukdoji Maharaj Nagpur University, Nagpur, Maharashtra, India 3 Department of Pharmaceutics, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi 110062, India http://crossmark.crossref.org/dialog/?doi=10.1208/s12249-025-03145-0&domain=pdf AAPS PharmSciTech (2025) 26:137 137 Page 2 of 30 [5]. Moreover, acute and chronic toxicities from adjuvant chemoradiotherapy in breast and gastrointestinal cancers are well-documented, including hematologic toxicity, mucosi- tis, and fibrosis [6–9]. It is thus significant to investigate complementary and alternative therapies that act on key mechanisms of cancer development with less toxicity [10, 11]. One of them is Epigallocatechin gallate (EGCG), one of the major polyphenolic constituents of green tea [12]. EGCG stands out among green tea polyphenols such as catechin, epicatechin, epigallocatechin, and gallic acid for its superior anticancer efficacy. In a head-to-head in vitro comparison on colorectal cancer (CRC) cell lines HCT-116 and SW480, EGCG exhibited the strongest antiproliferative activity, reducing cell viability by over 80%, compared inhi- bition by catechin (C) or epicatechin (EC) [13]. Additionally, EGCG induced G1-phase cell cycle arrest and significantly promoted apoptosis versus negligible effects by other tested compounds. This enhanced potency is structurally linked to the presence of the gallate moiety at the 3-position, which increases its ability to bind molecular targets and promote pro-apoptotic pathways. EGCG also modulates specific molecular signaling pathways not broadly targeted by other polyphenols. For example, it binds the 67-kDa laminin receptor (67LR), leading to activation of protein phosphatase 2 A and downregulation of pro-survival signals, a mecha- nism demonstrated to significantly suppress tumor growth in vivo [14]. Furthermore, EGCG uniquely inhibits fatty acid synthase (FASN), a known oncogenic enzyme, surpassing other polyphenols like epigallocatechin and catechin gallate [15]. These quantitative and mechanistic findings underscore the rationale for selecting EGCG as a lead natural compound for anticancer therapy development. Genetic and epigenetic factors further complicate cancer progression and treatment resistance. For instance, promoter methylation in colon carcinogenesis silences tumor suppres- sor genes, while genetic variants in polyadenylation path- ways contribute to pan-cancer susceptibility [16]. EGCG has been studied intensively for its anticancer effects of broad- spectrum action, such as inhibition of tumor growth, metas- tasis, and induction of apoptosis in cancer cells [17–19]. Notably, EGCG modulates epigenetic pathways, reversing gene silencing by inhibiting DNA methyltransferases, and exhibits genetic variability in toxicity profiles, as observed in hepatotoxicity susceptibility among populations. EGCG has been shown to suppress cancer cell growth, migration, and angiogenesis in various models of cancer, such as pan- creatic cancer and glioblastoma. Most synthetic chemother- apy agents are not like EGCG – it is selectively cytotoxic, non-toxic to normal cells and toxic to cancer cells [20–22]. Mechanistically, it exerts its anticancer effects by regulat- ing other important cellular signaling pathways such as those that control apoptosis (via the pro-apoptotic proteins Bax and caspase-3), cell cycle arrest (by inhibiting cyclin dependent kinases), and angiogenesis by suppressing the vascular endothelial growth factor pathways [23–26]. It can also desensitize the drug resistance through the inhibition of molecular chaperones like glucose-regulated protein 78 (GRP78) and epigenetic modifiers such as DNA methyl- transferases and histone acetyltransferases [27–29]. Despite its therapeutic potential, clinical use of EGCG is hindered by several pharmacokinetic limitations [30]. These involve its low bioavailability, rapid degradation in biological environments, and low systemic retention [31, 32]. EGCG is very metabolized when administered orally, and it exhibits poor plasma levels that render its therapeutic action in vivo impossible. Optimization of the clinical utility of EGCG in cancer biology is dependent on overcoming its pharmacokinetic limitations [33, 34]. Nanotechnology addresses these challengesof free EGCG and the protective function of encapsulation [89]. Additionally, serum proteins significantly affect nano- particle behavior in systemic circulation. Choi et al. (2010) showed that nanoparticles with physically assembled shells released their cargo more quickly in the presence of serum proteins compared to those with chemically crosslinked shells. Specifically, in vitro release of vascular endothelial growth factor (VEGF) from non-crosslinked nanoparticles decreased substantially in serum, whereas photo-crosslinked particles maintained their release profile, indicating that serum proteins can disrupt nanoparticle integrity unless chemically stabilized [244]. Further evidence by Li et al. (2014) supports this, where EGCG-loaded BSA nanoparticles coated with poly-ε-lysine or chitosan exhibited enhanced stability and delayed release of EGCG in gastric and intestinal fluids. Coated nanoparti- cles were particularly resistant to pH-induced aggregation at acidic pH (4.5–5.0) but showed instability at neutral pH (~ 7.0), again highlighting the importance of pH in nanoparticle design [245]. Moreover, Wu et al. (2013) found that sele- nium nanoparticles dispersed with EGCG aggregated signif- icantly at gastric pH (1.0), losing their nano-characteristics. This aggregation led to a ~ 39% reduction in bioavailability compared to albumin-dispersed counterparts, showing how protonation of EGCG in acidic environments diminishes nanoparticle integrity and systemic absorption [246–248]. In another study, although promising, EGCG nanotech- nology-mediated cancer treatment is hindered by various limitations, including low bioavailability and chemical insta- bility. Although fluorine-substituted EGCG nanoparticles enhance stability and targeted delivery, long-term therapeu- tic efficacy is not well explored. While microfluidic-based synthesis enhances nanoparticle homogeneity and stability, the problem of mass production and reproducibility hinders translational application to the clinical field [249]. Poor Biodistribution and Rapid Clearance Systemic administration of EGCG nanoparticles is gener- ally marred by inferior biodistribution and rapid clearance. The problem was demonstrated in a study of EGCG-func- tionalized gold nanoparticles against prostate cancer. Intra- tumoral administration successfully confined nanoparticles in the tumor tissue for 24 h, while systemic administration was characterized by rapid clearance, greatly limiting the therapeutic activity [197, 250]. Similarly, nanotechnology- delivery systems of EGCG are also promising for the treat- ment of colon cancer, but before clinical translation, some complications must be addressed. Low bioavailability and extensive systemic clearance of EGCG limit its therapeutic Ta bl e II ( co nt in ue d) Pa th w ay Pr im ar y Fu nc tio n EG C G A ct io n Eff ec t o n C an ce r Ex pe rim en ta l m od el Ex pe rim en ta l E vi de nc e/ stu dy Re fe re nc es V EG F Pr om ot es v as cu la r g ro w th an d tu m or a ng io ge ne si s D ow nr eg ul at es V EG F ex pr es si on a nd in hi bi ts an gi og en es is Su pp re ss es tu m or v as cu la ri- za tio n an d m et as ta si s H U V EC e nd ot he lia l c el ls EG C G in hi bi te d V EG F- in du ce d tu be fo rm at io n in H U V EC s a nd re du ce d an gi og en es is in x en og ra ft m od el s [1 89 ] p5 3 C on tro ls c el l c yc le a rr es t, D N A re pa ir, a nd a po pt os is St ab ili ze s a nd a ct iv at es p 53 by su pp re ss in g M D M 2 In du ce s a po pt os is a nd su p- pr es se s t um or g ro w th M C F- 7 br ea st ca nc er c el ls EG C G e nh an ce d p5 3 st ab il- ity , l ea di ng to a po pt os is a nd re du ce d pr ol ife ra tio n [1 90 , 1 91 ] AAPS PharmSciTech (2025) 26:137 Page 17 of 30 137 effects, which requires new drug formulations with stability maintenance and extended circulation time. Also, off-target toxicity due to non-specific biodistribution happens, and problems such as enzyme degradation and heterogeneous release rates within the gastrointestinal tract remain areas of concern for efficacy. To circumvent such shortcomings, however, future studies need to be directed towards the con- struction of advanced delivery systems that will effectively Table III Clinical Trials of EGCG in Cancer Treatment Cancer Type Sample Size Intervention Methodology Key Outcomes Reference Breast Cancer 180 Topical EGCG (660 μmol/L) vs. placebo Grade 2 + radiation dermatitis reduced from 72.2% to 50.5% (P = 0.008) [213] Esophageal Cancer 44 EGCG (440 μM) during chemoradio- therapy Significant reduction in RTOG scores and esophagitis-related pain [214] Thoracic Cancer 19 Topical EGCG (660–2574 μmol/L) Grade III RID decreased to grade I/II in 3 days; no adverse events [215] Breast Cancer 49 Topical EGCG from grade I derma- titis onset 85.7–89.8% reduction in dermatitis symptoms [216] Head and Neck Cancer 20 EGCG mouthwash (440 μmol/L) Reduced mucositis-related pain (P tumors was severely impaired. The extracellular matrix (ECM) was compact and blocked efficient nanoparticle penetration, as did the chaotic tumor vasculature [252]. One of the major draw- backs of EGCG nanotechnology for cancer therapy is the ability to bypass the problem of limited penetration into the TME. Elevated interstitial pressure, impaired vasculature, and stiff ECM significantly impede nanoparticle delivery. For instance, FEGCG/Zn nanocomplexes had good immune checkpoint modulation and therapeutic efficacy, but their efficacy was impaired by limited tumor penetration due to impaired vasculature and dense ECM, which subsequently reduced their therapeutic efficacy [253]. Scale‑Up and Translation to Clinical Use Scale-up clinical production continues to be an issue. For- mulated nanoethosomes of EGCG for melanoma transder- mal therapy proved to be superior in vitro and in animal studies. Batch-to-batch homogeneity and stability problems were however making large-scale production challenging. The regulatory as well as the quality control hurdle also restricted clinical translation[200]. Conversely, EGCG-loaded nanogels intended for mela- noma therapy in preclinical models exhibited delayed drug release and enhanced bioavailability. Nevertheless, their clinical application was hindered by the production cost and the challenge of synthesizing homogeneous bulk synthesis [254]. Regulatory and Safety Challenges Due to their unique characteristics, nanoparticles pose cer- tain regulatory issues. It is of great importance to ensure the safety of EGCG nanocarriers, although not much intensive research on their biocompatibility, degradation products, and potential immunogenicity has been done. Selenium nanopar- ticles encapsulated with EGCG peptides were the focus of experiments that highlighted the importance of rigorous test- ing to confirm that such preparations will not induce immune responses or deposit in off-target tissues [255, 256]. Overcoming Limitations of Nanotechnology in EGCG Delivery for Cancer Therapy Minimizing Toxicity and Improving Biocompatibility To avoid the possibility of toxicity of nanocarriers, scientists are formulating biocompatible and biodegradable materials. Polymers like chitosan and PLGA are potential candidates because they are well safe and biodegradable too [257]. PLGA nanoparticles were successful in EGCG delivery with reduced toxicity in lung cancer models [155]. Besides, biocompatible surface films such as polyethylene glycol (PEG) have been able to prevent later immune recognition and enhance circulation half-lives, for instance, EGCG- nanoethosome platforms for the therapy of melanoma [200]. Enhancing Drug‑Loading Efficiency and Stability Sophisticated nanoparticle production techniques such as electrospray encapsulation and solvent evaporation may potentially improve drug-loading and stability. EGCG nanoparticles prepared by a double-emulsion technique, for instance, exhibited excellent encapsulation efficiencies above 85% and sustained drug release without preliminary degradation [258, 259]. The nanoparticles stability was maintained by stabilizers like zinc ions or antioxidants being added into the nanoparticles'matrix. In research studies, FEGCG/Zn nano assemblies were shown to illustrate that zinc repressed EGCG degradation in natural conditions and thus was more efficacious in delivery to cancer cells [260]. Improving Biodistribution and Reducing Rapid Clearance Targeting the ligand surface modifications can remarkably enhance nanoparticle deposition to tumor locations. For example, folate-targeted nanoparticles bind specifically to folate receptors that are overexpressed in most cancer cells. Folate-decorated EGCG-loaded PLGA nanoparticle studies reported increased tumor accumulation with fewer off-target effects in breast cancer models [261] [88]. In addition, nanoparticles with extended circulation can be obtained by PEGylation or red blood cell membrane coat- ing. These methods minimize nanoparticle clearance by the mononuclear phagocyte system, allowing for maximum systemic biodistribution and extension of circulation time [262]. Overcoming Tumor Microenvironment Barriers Breaking through physical obstacles of dense tumor micro- environments (TME) can be achieved by the use of tiny AAPS PharmSciTech (2025) 26:137 Page 19 of 30 137 nanoparticles (Mohammad Qutub: Conceptualization, literature review, original draft preparation. Ujban Md Hussain: Methodology design, data analysis, critical revisions. Amol Tatode: Supervision, project administration, manuscript editing. Tanvi Premchandani: Data collection, figure preparation, reference management. Rahmud- din Khan: Scientific validation, manuscript review. Milind Umekar: Resources provision, critical review, overall guidance. Jayshree Tak- sande: Manuscript structure development, proofreading, final approval. Priyanka Singanwad: Literature curation, graphical abstract design, editing support. All authors have read and approved the final version of the manuscript. Funding NA. Data Availability Not applicable. Declarations Ethical Approval NA Informed Consent NA Clinical Trial Registration Number NA Conflict of Interest None. References 1. Cancer [Internet]. [cited 2025 Apr 24]. Available from: https:// www. who. int/ news- room/ fact- sheets/ detail/ cancer 2. Global cancer burden growing, amidst mounting need for ser- vices [Internet]. [cited 2025 Apr 24]. 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EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/ GLI, and TRAIL Mediated Signaling Pathways. Cancers (Basel) [Internet]. 2020 [cited 2025 Jan 28];12. Available from: https:// pubmed.by enhanc- ing EGCG’s stability and targeting. For example, nano- liposomes protect EGCG from acidic degradation in the gastrointestinal tract, while polymeric nanoparticles ena- ble sustained release and prolonged circulation. REDOX- responsive nanocarriers further improve precision by releasing EGCG selectively in tumor microenvironments with elevated oxidative stress [35, 36]. These nanocarriers also protect EGCG from enzymatic degradation, prolong its half-life in circulation, and allow for controlled drug release. For instance, nanocarriers have been shown to extend EGCG's plasma half-life from minutes to several hours and increase its systemic exposure by over five- fold compared to free EGCG. Nanocarriers also exploit the enhanced permeability and retention (EPR) effect of tumors, allowing EGCG to preferentially accumulate in tumor tissues while sparing healthy cells. By prevent- ing enzymatic degradation of EGCG, these drug delivery systems provide a sustained therapeutic effect. In addi- tion, their ability to modulate drug delivery at the site within the acidic tumor microenvironment (TME) guar- antees reduced systemic toxicity [37–39]. Notably, pH- responsive nanoparticles have been shown to be able to deliver EGCG selectively into cancer tissue without caus- ing off-target toxicity. Also, conjugating nanoparticles with tumor-targeting monoclonal antibodies or ligands has further enhanced the specificity of EGCG delivery, which further enhances its anticancer activity [40–42]. This review provides data gathered from preclinical and clinical research to discuss the pioneering contri- butions of nanotechnology in developing EGCG-based cancer treatments. The review also approximates current loopholes and loopholes in scientific research and pre- dicts a direction for future research to incorporate EGCG nanoformulations into practical clinical therapies. The review is a valuable resource to scientists, clinicians, and policymakers interested in integrating bioactive com- pounds such as EGCG into standard cancer treatment AAPS PharmSciTech (2025) 26:137 Page 3 of 30 137 protocols. Its major strength is the in-depth overview of the molecular mechanisms of the anticancer effects of EGCG and nanotechnology innovations breaking its pharmacokinetic and pharmacodynamic barriers. In addi- tion, the current paper addresses the synergistic effect that is achieved when EGCG is coadministered with other chemotherapeutic agents or immune modulators, thus pro- viding important insights into the potential directions of combination therapies. Molecular Mechanisms of EGCG in Cancer Treatment EGCG downregulates some Matrix metalloproteinases (MMPs) (MMP2, MMP7, MMP9, MMP12) through the modulation of transcription factors AP, Sp1, and NF-κB, via ROS signaling pathways (Fig. 1). Yamakawa et al. (2004) demonstrated that EGCG directly inhibits membrane-type 1 MMP (MT1-MMP), impairing angiogenesis both in vitro and in vivo, which led to reduced tumor growth in colon and sar- coma models [43]. Similarly, Chen et al. (2016) and Li et al. (2014) confirmed that EGCG treatment reduces MMP-2 and MMP-9 expression and activity, thereby suppressing migra- tion and invasion in renal carcinoma and glioma cells, respec- tively [44, 45]. Tanabe et al. (2023) investigated that EGCG binds MMPs directly, inhibits their activation, and inhibits inflammatory cytokine production such as TNFα and IL-1β, which in turn inhibit MMP activity [46]. EGCG exhibits excellent anticancer activity by modulat- ing several pathways that influence apoptosis, cell prolif- eration, metastasis, and drug resistance. In the research of Cheng et al. (2020), EGCG selectively induces apoptosis in HCC cells by activating pro-apoptotic proteins like Bax and caspase-3 while inhibiting anti-apoptotic proteins like Bcl-2 simultaneously, without any side effects on non-cancerous liver cells (Fig. 2) [47]. EGCG has been shown to exert a strong inhibitory effect on the epidermal growth factor recep- tor (EGFR) signaling pathway in lung cancer cells, contrib- uting to antiproliferative activity and cell cycle arrest. Ma et al. (2014) reported that EGCG significantly suppresses EGFR activation in human lung cancer cells by reducing both ligand-induced EGFR phosphorylation and total EGFR expression. Specifically, short-term EGCG treatment reduced phosphorylation of EGFR, AKT, and ERK1/2, while long- term treatment suppressed EGFR nuclear localization and downregulated cyclin D1, a key downstream target that regu- lates G1/S progression [48]. Additional evidence by Sun et al. (2022) using a synthetic dimeric EGCG (PBOG) further sup- ports that EGCG analogs bind directly to the EGFR ectodo- main and alter its secondary structure, effectively suppressing EGFR phosphorylation and its downstream signaling. This resulted in inhibited proliferation, enhanced apoptosis, and G1 arrest in NCI-H1975 lung cancer cells, a model of non- small cell lung cancer (NSCLC) [49]. Moreover, EGCG has shown synergistic effects when combined with EGFR tyrosine kinase inhibitors. For instance, Zhang et al. (2006) found that combining EGCG with erlo- tinib significantly reduced EGFR and AKT phosphorylation, induced G1 cell cycle arrest, and enhanced apoptosis in squa- mous cell carcinoma models, resulting in substantial tumor growth inhibition in vivo [50–52]. EGCG was also demon- strated to reverse drug resistance via inhibition of GRP78, a molecular chaperone that has been involved in chemoresist- ance [50, 53]. Xia et al. (2021) revealed that EGCG binds to the ATP-binding site of GRP78 and thereby inhibits its anti- apoptotic function to induce etoposide-activated apoptosis in breast cancer cells. Reversal of chemotherapy resistance by EGCG is a revolutionary breakthrough in cancer therapy, correcting an unmet clinical issue [54, 55]. Recent structural and computational studies provide strong evidence support- ing this mechanism. Bhattacharjee et al. (2015) conducted comprehensive molecular docking and molecular dynamics simulations which demonstrated that EGCG binds directly and stably to the ATPase domain of GRP78. Using tools such as AutoDock Vina and GROMACS, they identified specific amino acid residues Ile61, Glu293, Arg297, and Arg367 that play major roles in forming strong hydrogen bonds and hydrophobic interactions with EGCG. These residues are unique to GRP78 compared to related HSP70 proteins, pro- viding a molecular basis for EGCG's binding specificity and higher selectivity for GRP78 [56]. Binding energy analyses further confirmed that EGCG exhibits greater stability and more favorable energetics at the ATP-binding site than other known inhibitors like OSU-03012. Functionally, this bind- ing inhibits GRP78’s ATPase activity, which is essential for its chaperone function. Ermakova et al. (2006) showed that EGCG binding results in the structural conversion of GRP78 from its active monomer form into inactive dimers and oli- gomers. This conformational change disrupts its interaction with caspase-7, a key effector of apoptosis, thereby restoring apoptotic signaling pathways that are typically suppressed in chemotherapy-resistant cells. The same study demonstrated that EGCG significantly enhanced the cytotoxic effect of etoposide in breast cancer cells by preventing GRP78 from forming protective complexes with apoptotic regulators, effectively sensitizing the cells to drug-induced death [57]. In vivo validation further supports these molecular findings. Wu et al. (2022) reported that EGCG, in combination with irinotecan, markedly enhanced chemosensitivity in CRC xen- ografts. In this study, EGCG-induced upregulation of endo- plasmic reticulum (ER) stress and GRP78-mediated unfolded protein response (UPR) contributed to increased apoptosis and reduced tumor burden. 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Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. https://doi.org/10.1007/s12035-024-04015-9 https://doi.org/10.1007/s12035-024-04015-9 https://www.mdpi.com/1422-0067/24/11/9375/htm https://www.mdpi.com/1422-0067/24/11/9375/htm https://doi.org/10.1080/07373937.2023.2167827 https://doi.org/10.1208/s12249-023-02502-1 https://doi.org/10.1208/s12249-023-02502-1 Nano-Engineered Epigallocatechin Gallate (EGCG) Delivery Systems: Overcoming Bioavailability Barriers to Unlock Clinical Potential in Cancer Therapy Abstract Introduction Molecular Mechanisms of EGCG in Cancer Treatment Barriers to the Efficacy of EGCG in Cancer Therapy Poor Bioavailability and Rapid Metabolic Clearance Limited Tumor Accumulation and Penetration Inconsistent Regulation of Molecular Targets Resistance Mechanisms and Tumor Adaptation Role of Nanotechnology in EGCG Delivery Impact of Design and Synthesis of Nanoformulations on Enhanced Anticancer EGCG Delivery Functionalization and Targeting of Nanocarriers for EGCG Delivery Stimuli-Responsive Delivery Systems for EGCG Mechanisms of EGCG Nanoformulations in Anticancer Efficacy Enhanced Bioavailability and Cellular Uptake Synergistic Effects Apoptotic Pathways Activation Reduction in Tumor Growth and Angiogenesis Evidence of Nanotechnology in EGCG Delivery for Cancer Preclinical Evidence Clinical Evidence Limitations of Nanotechnology in EGCG Delivery for Cancer Therapy Toxicity and Biocompatibility of Nanocarriers Limited Drug-Loading Efficiency and Stability Poor Biodistribution and Rapid Clearance Challenges with Tumor Microenvironment Penetration Scale-Up and Translation to Clinical Use Regulatory and Safety Challenges Overcoming Limitations of Nanotechnology in EGCG Delivery for Cancer Therapy Minimizing Toxicity and Improving Biocompatibility Enhancing Drug-Loading Efficiency and Stability Improving Biodistribution and Reducing Rapid Clearance Overcoming Tumor Microenvironment Barriers Scaling Up for Clinical Applications Ensuring Safety and Regulatory Compliance Conclusion Referencesas a molecular target of EGCG [58]. AAPS PharmSciTech (2025) 26:137 137 Page 4 of 30 In clinical contexts, these molecular mechanisms correlate with improved outcomes. For example, a clinical study by the same group reported that EGCG administration in breast cancer patients undergoing radiotherapy resulted in reduced angiogenesis markers and increased tumor cell apoptosis [59]. Similarly, Guo et al. (2006) found that apoptosis and angiogen- esis markers were predictive of better prognosis in HCC, sup- porting the translational value of EGCG’s mechanisms [60]. Probably the most hopeful such advance is the design of Pro-EGCG, an optimal prodrug derivative with better drug- like characteristics than its parent compound [61] Landis- Piwowar et al. (2007) concluded that Pro-EGCG was more bioavailable and effective as a proteasome inhibitor and could effectively inhibit tumor growth in models of human breast cancer xenograft [62, 63]. In addition to being an anti-tumor suppressor, EGCG was also shown to reverse chemoresistance by various molecular mechanisms. Yuan et al. (2017) observed that EGCG suppressed multidrug resistance protein (MDR1) expression and concomitantly blocked the AKT/STAT3 pathway to restore oral cancer cell drug sensitivity to chemotherapy. Apart from its role against drug resistance, EGCG is also effective against epigenetic modulation [64]. Through the inhibition of DNA methyl- transferases and the disruption of histone acetylation, EGCG is capable of reactivating tumor suppressor genes as well as repressing oncogenic pathways, further establishing itself as an anticancer agent [65–67]. Besides, EGCG takes on a dual role as a pro-oxidant and antioxidant in the modulation of reactive oxygen species (ROS) and hence triggers apoptosis through ROS-mediated signaling [68–70]. Inhibition of metastasis is yet another significant char- acteristic of EGCG's anticancer properties. It is reported to downregulate MMP-2 and MMP-9 expression, which are crucial enzymes for tumor invasion and metastasis [71, 72]. Experiments using lung cancer (Zuo et al., 2017) and ovar- ian cancer (Xu et al., 2017) have ratified the MMP inhibi- tion capacity of EGCG, further indicating its consequent substantial suppressions of tumor migration and invasion capabilities [73, 74]. All these prove that EGCG possesses a functionality for the constraints on both local growth of a primary tumor as well as spread by metastases [75, 76]. Chronic inflammation is a recognized tumorigenic fac- tor, and the potent anti-inflammatory activity of EGCG is another factor in its therapeutic potency [77, 78]. It has been said to suppress transcription factors like NF-κB and AP-1, and initial inflammatory signaling pathways like the MyD88-dependent and Toll-interleukin-1 receptor domain- containing adaptor-inducing interferon-β (IFN-β) path- ways [79–82]. By blocking inflammatory mediators such as cyclooxygenase (COX), nitric oxide (NO) synthase, and TNF-α, EGCG interrupts the inflammation-cancer axis [83, 84]. As ROS are critical in NF-κB activation and result- ing inflammatory gene expression, EGCG's ROS-scaveng- ing property lies at the core of its anticancer mechanism [85–87]. Collectively, these mechanistic findings indicate EGCG's versatile function in cancer treatment, from drug resistance reversal, epigenetic reprogramming, metastasis inhibition, and anti-inflammatory regulation. With more studies, EGCG-based approaches are extremely promising for integration into standard therapies for cancer. Fig. 1 Role of Epigallocatechin gallate Nanoformulation in Preventing Cancer Metastasis and Inducing Tumor Shrinkage AAPS PharmSciTech (2025) 26:137 Page 5 of 30 137 Barriers to the Efficacy of EGCG in Cancer Therapy Poor Bioavailability and Rapid Metabolic Clearance The most fundamental barrier to the clinical effectiveness of EGCG is its low oral bioavailability, primarily due to poor intestinal absorption and rapid hepatic metabolism. EGCG undergoes extensive phase II metabolism, including glucu- ronidation, sulfation, and methylation, which significantly reduces the concentration of active compound in systemic circulation. In preclinical pharmacokinetic evaluations, orally administered free EGCG resulted in a very low peak plasma concentration (Cmax) and area under the curve (AUC). For instance, the AUC of free EGCG was measured at only 72.9 ± 14.7 μg·h/mL after a high oral dose, reflecting poor systemic exposure [88]. This limitation is compounded by EGCG’s instability in neutral and alkaline pH environments typical of the intesti- nal tract. Studies have demonstrated that EGCG loses over 50% of its structural integrity within one hour at physiologi- cal pH, primarily due to oxidative degradation and interac- tion with digestive enzymes [89]. Such rapid degradation means that only trace amounts reach systemic circulation, Fig. 2 Mechanism of Apoptosis Induced by (Epi)gallocatechin Gallate Nano Formulation AAPS PharmSciTech (2025) 26:137 137 Page 6 of 30 rendering oral delivery highly inefficient without protective formulation strategies. Limited Tumor Accumulation and Penetration Even when EGCG reaches systemic circulation, its distribu- tion to tumor tissues is suboptimal. EGCG lacks inherent targeting capability, leading to widespread biodistribution rather than preferential tumor accumulation. Moreover, the TME characterized by high interstitial pressure, dense col- lagen matrices, and abnormal vasculature presents physical barriers that limit deep drug penetration. A 2024 study by Zhou et al. tackled this issue by employ- ing EGCG to pre-condition the TME in triple-negative breast cancer (TNBC). EGCG disrupted collagen archi- tecture by blocking the TGF-β/Smad pathway, thereby improving tumor permeability. Subsequent administration of a nanotherapeutic (pHA@MOF-Au/MTX) resulted in a tumor inhibition rate of 79.9% and a 96.8% reduction in pulmonary metastasis, compared to significantly lower effi- cacy without EGCG pretreatment [90]. This illustrates that EGCG alone is insufficient for deep tumor penetration but may be valuable in combination with strategies that exploit its microenvironment-modulating properties. Inconsistent Regulation of Molecular Targets While EGCG interacts with a range of oncogenic pathways including NF-κB, PI3 K/Akt, and AMPK its downstream effects are often context-specific and sometimes paradoxical. In CRC cells, EGCG was unexpectedly shown to activate Yes-associated protein (YAP), a growth-promoting factor downstream of the Hippo pathway. YAP activation reduced the anti-tumor efficacy of EGCG, but this resistance could be reversed with pharmacologic inhibition of YAP [91]. This suggests that EGCG may have dual or opposing effects depending on cellular context, which complicates its thera- peutic predictability. Additionally, EGCG’s modulation of AMPK has been observed to trigger both pro-apoptotic and cytoprotective responses. In HT-29 colon cancer cells, EGCG activated AMPK, leading to downregulation of COX-2 and VEGF, key mediators of angiogenesis and inflammation. However, inhibition of AMPK abolished these effects, indicating that therapeutic outcomes are contingent on specific pathway dynamics [92]. Resistance Mechanisms and Tumor Adaptation Tumor cells may develop resistance to EGCG through a variety of adaptive mechanisms, including overexpression of efflux transporters (e.g., MRP1) and metabolic detoxification enzymes such as glutathione S-transferase (GST). A recent 2024 study demonstrated that EGCG was ineffective in high- glutathione tumors unless co-administered with a copper- EGCG nanocomposite. This system leveraged the tumor’s redox imbalance by depleting intracellular GSH and produc- ing ROS, restoring the compound’s cytotoxic potential [93]. Resistance also emerges via autophagy modulation. EGCG suppresses autophagyin some cancer models by targeting the Foxo3 transcription factor and downregulat- ing autophagy-related proteins like Bnip3 and LC3. While beneficial in contexts where autophagy supports tumor sur- vival, the inhibition may be less effective in tumors where autophagy acts as a suppressor of carcinogenesis. This dual- ity necessitates careful therapeutic alignment with tumor biology [94]. Role of Nanotechnology in EGCG Delivery The pharmacokinetic and mechanistic limitations of EGCG described earlier are not unique. Numerous clinically approved drugs initially faced similar issues poor solubil- ity, low stability, rapid clearance, and poor bioavailabil- ity but have successfully been reformulated or modified using advanced drug delivery technologies. Insights drawn from these approaches offer practical solutions to enhance EGCG’s therapeutic potential. Impact of Design and Synthesis of Nanoformulations on Enhanced Anticancer EGCG Delivery Nanoformulations have greatly improved the delivery of EGCG (Fig. 3) by improving its stability, bioavailability, and efficacy as a tumor-targeted drug [95]. A great example includes the research conducted by Tang et al. (2018), who synthesized chitin-based EGCG-functionalized nanoparti- cles for the targeted delivery of anticancer agent honokiol. These nanos exhibited a remarkable tumor inhibition rate of 83.55% against liver cancer in model experiments, much higher than free honokiol at merely 30.15% inhibition. This improved therapeutic efficacy proves the strength of nano- technology to maximize EGCG-based cancer treatments [96–99]. Likewise, the promise of polymer-based nanopar- ticles in improved pharmacokinetics of EGCG and activity synergism with delivery as co-drug therapy with chemo- therapeutics has also been highlighted, with increased bio- activity reported in cancer models [100–103]. Bhattacharya et al. (2024) prepared pH-sensitive poly- meric nanoparticles to treat colorectal cancer with 93% encapsulation efficiency and pH-responsive tumor-specific release. The nanoparticles showed great apoptosis and caused cell cycle arrest in colorectal cancer cells [104–107]. AAPS PharmSciTech (2025) 26:137 Page 7 of 30 137 The second approach was followed by Ding et al. (2018), where siRNA and EGCG were introduced to drug-resistant breast cancer cells via self-assembled nanogels. Targeted delivery system showed a great improvement in the thera- peutic effect, 15-fold cytotoxicity towards MDA-MB-231 resistant cells against EGCG alone. The above results reveal the effectiveness of multifunctional nanocarrier systems for evading the resistance mechanisms and, therefore, improving treatment efficacy tremendously [108]. One of the most extensively studied polymers in this context is poly(lactic-co-glycolic acid) (PLGA), known for its biocompatibility, biodegradability, and FDA approval for drug delivery applications. PLGA-based nanoparti- cles can encapsulate EGCG and protect it from premature degradation in the gastrointestinal tract and bloodstream, thereby improving both its stability and therapeutic win- dow. For example, in a study by Kazi et al. (2020), EGCG was encapsulated in PLGA nanoparticles that were surface- functionalized with a folate peptide to target folate receptor- overexpressing breast cancer cells (MDA-MB-231). These nanoparticles displayed high encapsulation efficiency (82.3%) and an average size of 175 nm. Importantly, in vitro studies showed that folate-conjugated EGCG-PLGA nano- particles exhibited significantly enhanced cellular uptake and cytotoxicity compared to both free EGCG and non- targeted nanoparticles. Enhanced uptake was attributed to folate receptor-mediated endocytosis, and the nanoparticles induced higher levels of mitochondrial depolarization and apoptosis. In vivo, the formulation achieved prolonged cir- culation and enhanced tumor accumulation, as confirmed by technetium-99 m radiolabeling and scintigraphic imaging, resulting in a superior antitumor response in MDA-MB-231 xenograft-bearing nude mice [88]. Another approach that has shown great promise involves dual-coated PLGA nanoparticles. In a study conducted by Wang et al. (2016), PLGA nanoparticles were coated with chitosan oligosaccharide (CO) and polyethylene glycol- poly(D,L-lactic acid) (PEG-PDLLA) to enhance colloidal stability, circulation time, and tumor penetration. The dual- coated nanoparticles had a near-neutral surface charge of + 3.54 mV and an average size of approximately 165.5 nm. These properties minimized rapid clearance by the mono- nuclear phagocyte system while promoting accumulation and diffusion within tumor interstitial spaces. In vitro, the nanoparticles exhibited greater intracellular uptake and cyto- toxicity compared to Taxol®, and in vivo, they demonstrated enhanced tumor accumulation and interstitial penetration in MDA-MB-231 xenograft models. These improvements were largely attributed to the synergistic effects of PEG-mediated steric stabilization and the mucoadhesive properties of chi- tosan, which together helped the nanoparticles bypass mac- rophage uptake and achieve higher tumor residence times [109]. The mechanisms underlying the enhanced anticancer activity of EGCG-loaded polymeric nanoparticles are mul- tifactorial. Improved cellular uptake is one of the primary mechanisms, facilitated by receptor-mediated endocytosis, pH- sensitive release in the tumor microenvironment, and nano- size-mediated passive targeting via the EPR effect. Once inter- nalized, the nanoparticles enable a controlled and localized release of EGCG within the cancer cells, thereby maximiz- ing its cytotoxic potential. Moreover, studies have shown that EGCG, when delivered via polymeric nanoparticles, can exert more potent inhibition on key oncogenic signaling pathways, such as NF-κB. This pathway is crucial in regulating genes associated with inflammation, proliferation, and resistance to apoptosis. Singh et al. (2011) demonstrated that EGCG encap- sulated in PLGA nanoparticles enhanced the chemosensitiza- tion potential of cisplatin in lung (A549), cervical (HeLa), and leukemia (THP-1) cancer cell lines. The nanoparticles not only increased the intracellular concentration of EGCG but also led to over 20-fold improvement in dose efficiency compared to free EGCG. Enhanced inhibition of NF-κB and downstream targets such as Bcl-2, COX-2, and VEGF was observed, result- ing in greater apoptosis, reduced angiogenesis, and inhibited metastasis [110]. Co-delivery systems have further expanded the utility of EGCG nanoparticles in cancer treatment. In one study, a co- loaded formulation of EGCG and 5-fluorouracil (5-FU) was developed using gelatin-chitosan nanoparticles decorated with wheat germ agglutinin (WGA) for colon cancer therapy. These nanoparticles displayed a sustained release profile, improved cellular uptake, and prolonged systemic circulation. The co- loaded nanoparticles showed significantly greater anti-tumor efficacy compared to single-drug or non-targeted formula- tions, demonstrating that the synergy between EGCG and chemotherapeutics can be maximized when co-encapsulated in targeted polymeric systems [111]. Polymer-based nanopar- ticles particularly those constructed from PLGA and modified with PEG, chitosan, or targeting ligands have demonstrated considerable success in enhancing the pharmacokinetics and bioactivity of EGCG. These formulations improve EGCG’s solubility, protect it from enzymatic degradation, and ensure selective and sustained release at tumor sites. The resulting bioactivity enhancements are due not only to increased cellular uptake and prolonged circulation time, but also to the ability of EGCG to more effectively engage and suppress oncogenic pathways such as NF-κB when delivered in nanoparticle form. Such systems exemplify the translational potential of nano- medicine in cancer therapeutics. Functionalization andTargeting of Nanocarriers for EGCG Delivery Targeted delivery systems proved to be very efficient in tar- geted delivery of EGCG to the cancer tissue and significantly AAPS PharmSciTech (2025) 26:137 137 Page 8 of 30 increase its chemopreventive action and decrease the sys- temic toxicity [112]. Sanna et al. (2017) have designed PSMA-targeted nanoparticles for prostate cancer targeting and achieved enhanced chemopreventive activity of EGCG by targeting tumor delivery [113]. Yuan et al. (2018) pre- pared fucose-grafted gold nanoparticles (GNPs) for the treatment of stomach cancer, which were more apoptotic and tumor-inhibiting compared to non-functionalized sys- tems [114]. Besides EGCG itself, conjugated nanocarrier systems have also been investigated for enhanced efficacy. GRPR- targeting ligand-grafted EGCG-loaded solid lipid nanopar- ticles, for instance, induced extreme inhibition of survival and tumor growth in mice [115, 116]. Besides, integrin receptor-specific and highly surface-expressed on breast cancer RGD-functionalized lipid carriers were constructed with the vision to target them and have already been shown to be an exceptionally potent approach towards targeted can- cer killing [117–121]. Stimuli‑Responsive Delivery Systems for EGCG Stimuli-responsive systems enable targeted and controlled release of EGCG [122–125]. Shafiei et al. (2015) developed EGCG-loaded layered double hydroxide (LDH) nanoparti- cles and demonstrated significantly enhanced anticancer effi- cacy against prostate cancer cells compared to free EGCG. The enhancement was quantitatively established through Fig. 3 Epigallocatechin Gallate Nano Formulation-Induced Apopto- sis in Cancer Cells. (The recognition molecules in the figure are the Y-shaped ligands on the nanoparticle surface that bind to cancer cell receptors, enabling receptor-mediated endocytosis. EGCG is encap- sulated inside the nanoparticle core, protected by polymers and an inorganic matrix that enhance stability and control its release. At step 3, the strands released into the cytoplasm represent EGCG and potentially co-delivered molecules like siRNA, which then trigger pro-apoptotic protein synthesis leading to cancer cell apoptosis. This nanoformulation improves EGCG’s targeting, bioavailability, and therapeutic action in tumors) AAPS PharmSciTech (2025) 26:137 Page 9 of 30 137 multiple metrics. The IC₅₀ value of EGCG-LDH nanoparti- cles was reported as 35.21 μg/mL, markedly lower than that of free EGCG at 176.34 μg/mL, indicating approximately fivefold higher potency. Apoptotic activity, assessed via annexin V-FITC/PI staining and flow cytometry, revealed a significant increase in late apoptosis for cells treated with the nanohybrids 34.3% compared to only 6.6% in the free EGCG group. Furthermore, MTT assays showed a greater time- and dose-dependent reduction in cell viability with EGCG-LDH nanoparticles. This enhanced cytotoxic effect was attributed in part to the pH-sensitive release behavior of the nanoparti- cles, with significantly higher EGCG release observed under acidic conditions (pH 4.8), mimicking the TME [126]. Near- infrared (NIR)-responsive mesoporous polydopamine nano- particles co-loading EGCG, diallyl trisulfide and indocya- nine green use a phase-change material as a thermosensitive gatekeeper, achieving precise NIR-triggered release and syn- ergistic apoptosis in breast cancer models [127]. Likewise, hollow gold nanocages encapsulating EGCG exploit NIR- induced photothermal effects to control payload release and amplify apoptotic signaling in hepatocellular carcinoma cells [128]. ROS-sensitive platformssuch as MnO₂-loaded PLGA particles that self-pressurize under H₂O₂ or thioketal-linked polymeric nanocomplexes that cleave in high ROS condi- tions actively discharge EGCG in oxidative tumor niches, bolstering antioxidant protection, chemodynamic therapy, and immunogenic cell death [129, 130]. Thermosensitive folate-modified nanospheres leverage temperature shifts to release EGCG and induce damage-associated molecular pat- terns in hepatocellular carcinoma [131], while pH-reversible borate ester-linked nano-frameworks disassemble in acidic tumor microenvironments to co-deliver EGCG and plati- num agents, enhancing ICD and PD-L1 checkpoint block- ade efficacy [132]. Iron-doped layered double hydroxide nanosheets further exemplify TME-responsive systems by releasing EGCG and Fe2⁺ under acidic conditions to acceler- ate Fenton reactions for cooperative chemo-chemodynamic therapy [133].Collectively, these multifunctional platforms significantly improve EGCG targeting, controlled release, and antitumor potency by tailoring drug delivery to light, thermal, oxidative, and pH stimuli. Mechanisms of EGCG Nanoformulations in Anticancer Efficacy Enhanced Bioavailability and Cellular Uptake Bioavailability and cellular uptake of EGCG, a polyphe- nolic anticancer agent, are typically restricted by its low solubility and stability in the physiological condition [134]. Nanotechnology drug delivery systems provide a potential solution to overcome the intrinsic limitations of EGCG by loading it into biocompatible carriers. PLGA nanoparticles, for instance, have led to enhanced bioavailability and site- specific targeting of tumors, thus enhancing the anticancer efficacy of EGCG in different forms of cancers [135, 136]. Moreover, lipid-based carriers like LB-SLNs have also shown to be effective in safeguarding EGCG from enzyme degradation with sustained release and improved therapeutic effect [137]. Applications of pH-sensitive nanocarriers have been extensively documented as well, as they can release EGCG selectively in the acidic tumor microenvironment, thus ensuring maximal therapeutic effect [138, 139]. In addi- tion, extracellular vesicles (EVs) were proved to be a novel platform for drug carriers, allowing enhanced tumor-target- ing efficacy, prolonged EGCG retention within the tumor microenvironment, and therapeutic effectiveness [140]. All of these indicate that nano formulations could potentially be key in surmounting the pharmacokinetic limitations of EGCG. For instance, free EGCG administered orally at a dose of 500 mg/kg resulted in a Cmax of 10.7 ± 1.1 μg/mL and an area under the plasma concentration–time curve (AUC) of 72.9 ± 14.7 μg·h/mL. In contrast, EGCG encap- sulated in a block-copolymer nanoparticle formulation increased the AUC to 578.5 ± 73.8 μg·h/mL and the Cmax to 49.3 ± 2.9 μg/mL representing an approximately eightfold improvement in systemic exposure [141]. Similarly, encapsulation of EGCG in albumin nanopar- ticles improved its pharmacokinetics substantially. In vivo studies demonstrated a 1.5-fold increase in plasma concen- tration and a prolonged elimination half-life (T₁/₂) of 15.6 h compared to free EGCG, which exhibited rapid clearance [142]. To enhance EGCG delivery, various nanocarriers have been explored. PLGA nanoparticles have demonstrated enhanced stability and tumor-specific accumulation, result- ing in improved bioavailability and anticancer efficacy in preclinical cancer models. Lipid-based solid lipid nano- particles (SLNs), such as LB-SLNs, have shown to protect EGCG from enzymatic degradation while enabling sustained drug release profiles. For example, SLNs improved EGCG encapsulation efficiency to over 80% and demonstrated sustained release kinetics consistent with Higuchi models, supporting effective diffusion-controlled release. In addi- tion, pH-sensitive nanocarriers have gained attention for their ability to selectively release EGCG in acidic tumor microenvironments, thereby increasing intratumoral drug concentrations while minimizing off-target exposure. Dual- drug-loaded nanoparticles combining EGCG with ascorbic acid demonstrated ~ fivefold higher brain EGCG concentra- tions between 5–25 h post-administration in an Alzheimer's model, supporting both enhancedretention and therapeutic efficacy [143, 144]. Moreover, emerging platforms such as EVs and protein- based carriers like β-lactoglobulin complexes have also dem- onstrated improved oral delivery and antioxidant activity. AAPS PharmSciTech (2025) 26:137 137 Page 10 of 30 In vivo rat studies with EGCG-β-lactoglobulin complexes showed a twofold increase in both Cmax and AUC compared to free EGCG, indicating improved absorption and meta- bolic stability [145]. Upcoming work will examine how the composition of the nanoparticle can differ, i.e., via incor- poration of stimulus-sensitive or multi-functional carriers, and how EGCG delivery and tumor retention are improved. Comparative analyses of several nanocarriers in the context of clinical feasibility will offer the insights regarding trans- lation ability. Synergistic Effects EGCG nanoformulations are typically co-formulated with other medications to capitalize on synergistic action during cancer treatment (Table I) [146]. Vieira et al. (2023) have reported that co-encapsulation of EGCG with curcumin in polymeric nanoparticles caused a significant induction of apoptosis in breast and lung cancer cells when compared to their individual use [147]. In addition, EGCG-loaded liposomes, in combination with nucleic acid therapeutics, exhibited increased inhibition of tumor cell proliferation in vitro [148]. Another study proved the capability of multi- functional nanocarriers in the delivery of EGCG in combina- tion with chemotherapeutic drugs to considerably increase the overall efficacy of the treatment [149, 150]. In addition, the role of the EPR effect towards nanocarriers was high- lighted, illustrating that it facilitates the retention of EGCG in tumors upon combining with anti-angiogenic agents [151, 152]. Further, the use of specially designed nanovectors for EGCG delivery in combination with immune modulators was investigated, and this resulted in enhanced immunity and tumor suppression [153, 154]. Overall, these studies reveal that nanotechnology can facilitate combinatorial therapy through the co-delivery of EGCG with synergistic drugs to enhance therapeutic efficacy. Moving forward, the research could focus on optimizing nanoparticle designs for the co-encapsulation of multiple agents while maintaining stability and sustained release profiles. Additionally, inves- tigating molecular mechanisms underlying synergistic inter- actions will help tailor combination therapies for specific cancer types. Apoptotic Pathways Activation Nanoformulated EGCG effectively activates apoptotic pathways, a critical mechanism for cancer cell death [166]. EGCG-loaded nanoparticles significantly upregulate pro- apoptotic proteins such as Bax and caspase-3 while sup- pressing anti-apoptotic Bcl-2 in hepatocellular carcinoma models [167, 168]. Similarly, multifunctional nanocarriers delivering EGCG alongside apoptotic inducers enhanced mitochondrial depolarization and cytochrome c release, accelerating apoptosis in resistant tumors [169, 170]. EGCG application in nanoemulsions was reported to induce apopto- sis pathways selectively in colon cancer cells without affect- ing normal tissues [171, 172]. EGCG delivery through nano- structured systems resulted in the production of higher levels of ROS in cancer cells, thereby enhancing the effectiveness of apoptosis induction [173]. Also, research has confirmed that nanocarriers modified with functionalities effectively increase EGCG delivery substantially, which augments its apoptotic pathway interactions with aggressive cancers [174] [175]. All of these confirm that EGCG nanoformulated con- tains enormous promise as a means to induce tumor cells to apoptosis targeting. However, further investigation would be required to determine the specific pathways targeted by EGCG nanoformulations and whether these are safe in the long term within normal tissues. The nanocarrier engineer- ing with a blend of EGCG with other pro-apoptotic drugs further augments therapeutic benefit. Reduction in Tumor Growth and Angiogenesis EGCG-loaded nanocarriers have shown great promise in inhibiting tumor growth and angiogenesis (Table II) [176]. Wang et al. (2019) found that EGCG-encapsulated nanopar- ticles showed enhanced tumor inhibition via VEGF pathway inhibition, which are key in angiogenesis [111]. Enhanced efficacy of pH-responsive nanocarriers for the delivery of EGCG inhibits tumor-associated angiogenesis with reduced systemic toxicity [177]. Chen et al. (2020) emphasized the role of surface-engineered nanoparticles in ensuring EGCG retention in tumor microenvironments to inhibit proteins related to angiogenesis more effectively [178]. Chitosan nanocarriers also enhanced anticancer activity of EGCG by targeting vasculature in tumors preferentially [179, 180]. Lastly, EGCG's anti-angiogenic effect was further enhanced by smart nanoparticle-based drug delivery systems, which strongly inhibited tumor vascularization [181, 182]. he results show the potential of nanotechnology to target angi- ogenesis more selectively than free EGCG. Future studies should be focused on developing tumor-specific nanocarriers that exploit the EPR effect without inducing cytotoxicity to off-target tissues. Additionally, clinical trials assessing the anti-angiogenic efficacy of EGCG nanoformulations will be critical to validate preclinical findings. Evidence of Nanotechnology in EGCG Delivery for Cancer Preclinical Evidence Nanotechnology has revolutionized the delivery of EGCG by overcoming its inherent challenges, such as poor AAPS PharmSciTech (2025) 26:137 Page 11 of 30 137 bioavailability and stability, to enhance its anticancer prop- erties (Table II) [192]. LDH nanoparticles to target pros- tate cancer cells has shown improved the anticancer activ- ity of EGCG by over fivefold compared to free EGCG and achieved sustained drug release under acidic conditions, mimicking the tumor microenvironment [126, 193]. Simi- larly, EGCG-loaded PLGA nanoparticles demonstrated enhanced cellular uptake and cytotoxicity against lung can- cer cells in vitro. Nanoparticle delivery systems of drugs have also shown immense potential in increasing the anti- cancer activity of EGCG. In a patient-derived xenograft model, EGCG-encapsulated nanoparticles showed strong tumor growth inhibition and offered a tenfold dose reduction compared to free EGCG, demonstrating their therapeutic efficacy [88] [194]. A preclinical trial using gold nanopar- ticles (AuNPs) functionalized with EGCG selectively tar- geted prostate cancer cells via laminin receptor interactions. Intratumoral delivery of the same EGCG-AuNPs yielded 80% volume reduction of tumors in 28 days, demarcating the effectiveness of such targeted therapy [195–197]. The same has been executed utilizing EGCG-filled chitosan nanoparticles, enhancing cytotoxicity and bioavailability immensely against melanoma cells. This system lowered the IC50 25-fold and sustained the drug release over a longer period with prolonged plasma half-life against free EGCG [198, 199]. The other novel approach was the use of EGCG nanoethosomes for melanoma treatment. These docetaxel co-loaded nanoparticles in a transdermal drug delivery sys- tem were found to induce a 31.5% rate of tumor suppression in mice and provide higher exposure to the tumor along with lower systemic toxicity [200, 201] Folate-targeted PLGA nanoparticles have also been constructed for the folate receptor-overexpressing breast cancer cells targeted therapy. These specific nanoparticles were more internalized, more cytotoxic to cancer cells, and more therapeutically effec- tive in preclinical models [202, 203]. These developments affirm the ability of nanotechnology to boost EGCG's thera- peutic efficacy by increasing targeting, bioavailability, and sustained drug release. Synthesis of EGCG-based nanotherapeutics will be a breakthrough incancer therapy with enhanced bioavailabil- ity and targeted delivery of drugs [204]. The innovation of this research was the synthesis of folate-conjugated PLGA nanoparticles capable of encapsulating EGCG for breast cancer treatment. The nanoparticles targeted folate receptors on cancer cells, which were overexpressed on cancer cells, with higher cellular uptake and apoptosis due to their inter- action. When used in preclinical models of breast cancer, their injection caused significant regression of the tumor and enhanced the therapeutic efficacy, and they demonstrated great potential for clinical application [88]. In xenograft models of human pancreatic cancer (AsPC- 1), EGCG minimized tumor burden and neovascularization and repressed MMPs of tumorigenic activity. Equivalently, in glioblastoma cells, EGCG abolished the induction of membrane-type 1 MMP (MT1-MMP), which is an impera- tive mediator of tumour invasion and migration, reiterating further its druglikeness [205, 206]. EGCG nanoethosomes were found to be a lead clinical candidate. In melanoma, co-delivery of docetaxel and EGCG through transdermal nanoparticles cut down tumor volume by 31.5% over 14 days. The method not only enhanced tumor targeting but also enhanced drug bioavailability and mini- mized systemic toxicity, with great clinical potential [100, 207]. In addition, a new EGCG-loaded selenium nanoparti- cle platform with Tet-1 peptides significantly increased cell uptake and inhibited oxidative stress in the tumor microen- vironment. By controlling oxidative processes and allevi- ating inflammation, this nanoplatform showed tremendous potential as targeted cancer therapy [208, 209]. Oral delivery of EGCG via biodegradable nanoparticles has also been investigated. EGCG-loaded PLGA nanopar- ticles proved to be a potential candidate for the treatment of lung cancer and were shown to possess greater thera- peutic efficacy than free EGCG, increased bioavailability, and longer plasma half-life. EGCG-nanoparticles were discovered to inhibit tumor growth strongly in preclinical models, that is, in PDX models, an important step toward clinical translation [155]. Clinical trials (Table III) have also exhibited the potential of EGCG nanomaterials in the therapy of breast cancer. For example, GRPR-conjugated nanostructured lipid carriers encapsulating EGCG exhib- ited increased cytotoxicity against breast cancer cells, sig- nificantly blocking tumor growth and enhancing survival in C57/BL6 mouse models. The results indicate that GRPR- targeted EGCG nanoparticles are promising in breast cancer therapy [210]. Likewise, folate receptor-targeted EGCG nan- oparticles (EGCG-T-NPs) showed enhanced antiprolifera- tive activities against PSMA + (22Rv1) prostate cancer cells overexpressing the folate receptor in prostate cancer. In 3D spheroid tumor models, the nanoparticles showed increased penetration into the tumor, enhanced cellular uptake, and mitochondrial depolarization, finally inducing apoptosis. The encouraging outcomes justify further preclinical studies on EGCG-T-NPs for the treatment of prostate cancer [211]. Furthermore, electrospray-encapsulated EGCG microparti- cles were clinically significant by virtue of controlled drug release and anti-inflammatory suppression in cancer models. The microparticles inhibited central inflammation-related mediators, hence validating their potential in clinical oncol- ogy [212]. Clinical Evidence EGCG has demonstrated potential in clinical cancer research due to its antioxidant, anti-inflammatory, and chemopreventive AAPS PharmSciTech (2025) 26:137 137 Page 12 of 30 Ta bl e I S yn er gi sti c Eff ec ts o f E G C G in C an ce r T he ra py : C om bi na tio n St ra te gi es a nd N an ot ec hn ol og y- B as ed D el iv er y Sy ste m s C an ce r T yp e C om bi na tio n A ge nt M ec ha ni sm o f s yn er gy O ut co m e N an ot ec hn ol og y- B as ed D el iv er y sy ste m Re fe re nc es Lu ng C an ce r ( N SC LC — A 54 9, H 12 99 ) PL G A -E nc ap su la te d EG C G In hi bi tio n of N F- κB a ct iv at io n, su pp re ss io n of N F- κB -r eg ul at ed ge ne s, in cr ea se d ce llu la r u pt ak e, en ha nc ed c yt ot ox ic ity 3– fo ur fo ld d os e ad va nt ag e, in cr ea se d ap op to si s, im pr ov ed an ti- tu m or e ffi ca cy in P D X m od el PL G A n an op ar tic le s ( 17 5. 8 ± 3. 8 nm ), oi l-i n- w at er e m ul si on so lv en t e va po ra tio n te ch ni qu e, en ca ps ul at io n effi ci en cy ~ 86 % [1 55 ] G as tri c C an ce r EG C G + si TM EM 44 -A S1 Si le nc in g ln cR N A T M EM 44 -A S1 re ve rs es 5 -F U re si st an ce b y ac ti- va tin g th e p5 3 si gn al in g pa th w ay C hi to sa n– ge la tin -E G C G n an op ar - tic le s e nh an ce d siT M EM 44 -A S1 de liv er y an d re ve rs ed 5 -F U re si st an ce , i m pr ov in g th er ap eu - tic e ffi ca cy C hi to sa n– G el at in -E G C G N an o- pa rti cl es [1 56 ] B re as t C an ce r EG C G + P ac lit ax el C o- de liv er y sy ste m e nh an ce s ap op to si s a nd re du ce s c el l i nv a- si on b y in hi bi tin g M M P- 2 an d M M P- 9 ac tiv iti es PT X /E G C G c o- lo ad ed li po so m es sh ow ed b et te r c yt ot ox ic ity , ap op to si s ( ca sp as e- 3 ac tiv ity ), an d re du ce d in va si ve ne ss c om - pa re d to in di vi du al d ru g- lo ad ed lip os om es Li po so m es [1 57 ] C an ce r A ny ty pe M el itt in (M PI ) & E G C G (F lu or i- na te d EG C G — FE G C G ) Fl uo rin e m od ifi ca tio n en ha nc es EG C G d el iv er y Sy ne rg ist ic e ffe ct th ro ug h re gu la - tio n of a po pt os is (B cl -2 /B ax ) an d im m un e pa th w ay s ( IR F, ST A T- 1/ pS TA T- 1, P D -L 1) In v iv o: S ig ni fic an t i nh ib iti on o f tu m or g ro w th In v itr o: E nh an ce d ap op to si s a nd re du ce d m ig ra tio n/ in va si on Fl uo ro -N an op ar tic le s: S el f- as se m - bl ed F EG C G a nd M PI [1 58 ] G lio m a (L N -2 29 , U 87 M G ) EG C G + M ag ne tic N an op ar tic le s (M N Ps ) EG C G e nh an ce s M N P up ta ke v ia in te ra ct io n w ith 6 7L R re ce pt or ; m ag ne tic fi el d fu rth er sy ne rg iz es in te rn al iz at io n by fa ci lit at in g na no pa rti cl e ag gr eg at io n an d in cr ea si ng v es ic le si ze EG C G si gn ifi ca nt ly e nh an ce s M N P in te rn al iz at io n, w ith m ag - ne tic fo rc e in cr ea si ng in te rn al - iz ed v es ic le si ze a nd n um be r D ex tra n- co at ed M N Ps (2 50 n m ) an d Fl ui dM A G -C M X (2 00 n m ) [1 59 ] B re as t C an ce r ( M C F7 ) EG C G (e nc ap su la te d in c hi to sa n- co at ed n an ol ip os om es ) C hi to sa n- co at ed n an ol ip os om es en ha nc e EG C G st ab ili ty , im pr ov e su st ai ne d re le as e, a nd in cr ea se in tra ce llu la r E G C G up ta ke in M C F7 c el ls C SL IP O -E G C G si gn ifi ca nt ly en ha nc es E G C G 's an tip ro lif er a- tiv e an d pr oa po pt ot ic e ffe ct s, es pe ci al ly a t 1 0 μM o r l ow er , w he re n at iv e EG C G h as n o be ne fic ia l e ffe ct s C hi to sa n- co at ed n an ol ip os om es (C SL IP O -E G C G ) [1 60 ] B re as t C an ce r EG C G (c on ju ga te d w ith B om besi n) EG C G is e nc ap su la te d in so lid lip id n an op ar tic le s ( SL N s) a nd co nj ug at ed w ith B om be si n to ta rg et g as tri n- re le as in g pe pt id e re ce pt or s ( G R PR ) o ve re xp re ss ed in b re as t c an ce r c el ls Pe pt id e- co nj ug at ed fo rm ul at io ns sh ow ed g re at er c yt ot ox ic ity to c an ce r c el ls a nd im pr ov ed su rv iv al a nd re du ce d tu m or vo lu m e in m ic e co m pa re d to no n- co nj ug at ed fo rm ul at io ns an d pl ai n EG C G So lid li pi d na no pa rti cl es (S LN s) co nj ug at ed w ith B om be si n [1 61 ] AAPS PharmSciTech (2025) 26:137 Page 13 of 30 137 Ta bl e I (c on tin ue d) C an ce r T yp e C om bi na tio n A ge nt M ec ha ni sm o f s yn er gy O ut co m e N an ot ec hn ol og y- B as ed D el iv er y sy ste m Re fe re nc es Lu ng C an ce r G em ci ta bi ne (G EM ) a nd E G C G G EM a nd E G C G a re lo ad ed in to so lid li pi d na no pa rti cl es (S LN s) fo r i nt ra na sa l d el iv er y, o ffe rin g a su st ai ne d re le as e pr ofi le a nd im pr ov ed d ru g ta rg et in g to th e lu ng s Th e G EM -E G C G S LN s e xh ib - ite d be tte r p ha rm ac ok in et ic s, ta rg et in g, a nd sa fe ty , w ith fe w er pa th ol og ic al le si on s a nd a lo w he m ol ys is ra te . H ig h dr ug ta rg et in g in de x fo r G EM a nd EG C G w as o bs er ve d So lid li pi d na no pa rti cl es (S LN s) [1 62 ] G lio m a (B ra in C an ce r) U rs ol ic a ci ds (U A ) a nd E G C G Th e fu nc tio na l l ip os om es a re de si gn ed to c ro ss th e bl oo d– br ai n ba rr ie r ( B B B ) a nd in du ce ap op to si s i n gl io m a ce lls a nd gl io m a ste m c el ls , e nh an ci ng dr ug d el iv er y to th e br ai n Th e lip os om es si gn ifi ca nt ly en ha nc e th e an ti- ca nc er e ffe ct s of U A a nd E G C G , p ro m ot in g ap op to si s a nd in hi bi tin g tu m or gr ow th in v itr o an d in v iv o M ul tif un ct io na l t ar ge tin g lip os om es [1 63 ] B re as t C an ce r ( ER + , P R + , H ER 2 + ) D ox or ub ic in (D O X ), Pr oc ya ni di n (P A ), EG C G Th e na no pa rti cl es ta rg et E R , P R , an d H ER 2 po si tiv e br ea st ca nc er ce lls v ia m ul ti- lig an d m od ifi ca - tio n, e na bl in g en ha nc ed ta rg et - in g an d sy ne rg ist ic d ru g de liv er y Th e na no pa rti cl es in hi bi t t he gr ow th o f v ar io us b re as t c an ce r ce lls (B T- 47 4, M C F- 7, E M T- 6, M D A -M B -2 31 ) b ot h in v itr o an d in v iv o M ul ti- lig an d m od ifi ed p ho sp ha ti- dy lc ho lin e (P C ) n an op ar tic le s (N P- ER , N P- ER -H ER 2, N P- ER - H ER 2- PR ) [1 64 ] Pa nc re at ic C an ce r EG C G , C yc lo pa m in e (C yA ) EG C G in hi bi ts E G FR p ho sp ho - ry la tio n, a nd C yA d ow nr eg u- la te s G li- 1 ex pr es si on , t ar ge tin g tw o ke y si gn al in g pa th w ay s i n pa nc re at ic c an ce r c el ls Th e co m bi na tio n of E G C G a nd C yA sh ow ed re m ar ka bl e gr ow th in hi bi tio n an d ap op to si s i nd uc - tio n in M ia P aC a- 2 ce lls M et ho xy p ol y( et hy le ne g ly co l)- b- po ly [5 -m et hy l-5 -( 3, 4 , 5- tri m et ho xy be nz oy ol )− 1, 3- di ox an -2 -o ne -c o- la ct id e] (m PE G -b -P (T M -c o- LA )) co po ly m er ic m ic el le s [1 65 ] AAPS PharmSciTech (2025) 26:137 137 Page 14 of 30 properties. Preclinical studies suggest EGCG modulates sign- aling pathways involved in carcinogenesis, apoptosis, and angiogenesis. Clinical trials have explored its efficacy in miti- gating treatment-related toxicities and as an adjunct therapy across multiple cancer types. Below (Table III) is a summary of key clinical trials investigating EGCG in oncology, derived from peer-reviewed studies. Limitations of Nanotechnology in EGCG Delivery for Cancer Therapy Nanotechnology has emerged as a promising approach for improving the bioavailability and therapeutic efficacy of EGCG in cancer treatment. However, several challenges and limitations still hinder its broader application. Below are the detailed limitations categorized under specific challenges. Toxicity and Biocompatibility of Nanocarriers While nanotechnology improves EGCG delivery, the poten- tial toxicity of some nanocarriers remains a major concern. A study investigating a core–shell nanosystem combining EGCG and ursolic acid reported enhanced tumor targeting for hepatocellular carcinoma, but the long-term effects of these nanoparticles on healthy tissues were unclear. Persis- tent toxicity and accumulation in the liver, spleen, or kidneys could limit their clinical application [238]. In a 2021 study by Peng et al., EGCG was encapsulated in brain-targeting nanoparticles modified with the RD2 peptide and adminis- tered intravenously to an Alzheimer’s disease mouse model over a 28-day period. The nanoparticles exhibited a mean particle size of 204.83 ± 2.80 nm, a zeta potential of − 23.88 mV, and a high encapsulation efficiency of 94.39%. Notably, histopathological analysis using hematoxylin–eosin (HE) staining revealed no evidence of organ damage in major tissues, including the liver, spleen, kidneys, lungs, and heart. The treatment not only improved cognitive function and reduced neuroinflammation but also demonstrated an absence of organ-specific toxicity over the 4-week exposure, suggesting a favorable short-term safety profile [239]. Another in vivo investigation by Zhang et. al (2018) evaluated pH-sensitive polymeric nanoparticles loaded with EGCG in a nephrotic syndrome rat model over a 6-week period. These nanoparticles, averaging 91.3 ± 0.8 nm in size with an encapsulation efficiency of 80.8% and a drug loading capacity of 6.3%, significantly altered the pharmacokinetics of EGCG. Treated rats showed a 2.4-fold increase in bioa- vailability compared to EGCG in powder form. Importantly, pathological assessments revealed reduced proteinuria and significantly lower kidney pathology scores in rats treated with the EGCG nanoparticles compared to those receiving free EGCG, indicating reduced renal damage. This finding reinforces the therapeutic potential of EGCG-loaded nano- particles while supporting their renal safety under moderate- term exposure conditions [240]. Nonetheless, while these studies report short to moderate- term safety, the question of long-term bioaccumulation and toxicity remains partially unanswered. For example, gold nanoclusters have demonstrated organ-specific retention over extended periods. In a study by Zhang et al. (2012), GSH- protected gold nanoclusters exhibited efficient renal clear- ance, with 36% of the administered dose excreted within 24 h and 94% metabolized over 28 days. These nanoclusters initially caused acute kidney and immune responses; how- ever, all adverse effects were resolved by day 28. In contrast, BSA-protected gold nanoclusters, which formed larger aggre- gates, showed less than 5% clearance, remained in the liver and spleen for weeks, and caused persistent organ toxicity [241]. Another study on EGCG-loaded selenium nanopar- ticles coated with peptides to enhance cellular uptake noted that, while the nanoparticles reduced oxidative stress and inflammation,their safety profile under long-term exposure required further investigation [242]. Taken together, while available studies show that EGCG-loaded nanoparticles can offer therapeutic benefits without causing acute or subacute organ toxicity, comprehensive long-term in vivo evaluations remain limited. Future research must systematically assess biodistribution and chronic exposure effects, especially focusing on the liver, spleen, and kidneys, to ensure the clini- cal viability and biosafety of these nanocarriers. Limited Drug‑Loading Efficiency and Stability Nanoparticle formulations often face challenges in achieving optimal drug-loading capacity and stability. Among the most critical factors, physiological pH, especially under neutral to alkaline conditions, markedly destabilizes EGCG. Rad- hakrishnan et al. (2016) demonstrated that EGCG is highly unstable at physiological pH (~ 7.4), with rapid degradation observed in aqueous solutions. The study found that unen- capsulated EGCG degraded quickly under alkaline condi- tions, necessitating encapsulation within lipid nanoparticles to enhance its bioavailability and cytotoxicity against cancer cells. EGCG-loaded lipid nanoparticles exhibited signifi- cantly increased cytotoxicity 8.1 times higher against MDA- MB-231 breast cancer cells compared to free EGCG high- lighting how improved stability via encapsulation directly correlates with enhanced therapeutic action [243]. Digestive enzymes also present a destabilizing threat to nanoparticle integrity. A study by Zou et al. (2014) evaluated the degrada- tion of EGCG in simulated intestinal fluid (SIF) both in the presence and absence of pancreatin. EGCG encapsulated in nanoliposomes retained 31.2% to 47.7% of its original con- tent after 1.5 h of incubation, whereas free EGCG showed degradation to just 3.4–3.5% under the same conditions. AAPS PharmSciTech (2025) 26:137 Page 15 of 30 137 Ta bl e II T he R ol e of E G C G in M od ul at in g K ey S ig na lin g Pa th w ay s i n C an ce r P re ve nt io n an d Th er ap y Pa th w ay Pr im ar y Fu nc tio n EG C G A ct io n Eff ec t o n C an ce r Ex pe rim en ta l m od el Ex pe rim en ta l E vi de nc e/ stu dy Re fe re nc es PI 3 K /A kt /m TO R in hi bi ts a po pt os is b y bl oc k- in g th e fu nc tio n of p ro - ap op to tic B cl -2 p ro te in s; re gu la te s p ro te in sy nt he - si s a nd c el l g ro w th v ia m TO RC 1 ac tiv at io n In hi bi ts A kt a nd m TO R a ct i- va tio n by p ho sp ho ry la tio n, in cr ea se s P TE N e xp re ss io n, an d su pp re ss es P I3 K /A kt si gn al in g Su pp re ss es c el l p ro lif er at io n, in du ce s a po pt os is , r ed uc es tu m or g ro w th O va ria n an d pa nc re at ic c an - ce r c el l l in es EG C G tr ea tm en t r ed uc ed tu m or si ze a nd p ro lif er at io n in o va ria n ca nc er c el ls b y bl oc ki ng A kt /m TO R si gn - al in g an d en ha nc in g PT EN ex pr es si on [1 74 ] N rf -2 /H O -1 C on tro ls a nt io xi da nt re sp on se ; p ro te ct s c el ls fro m o xi da tiv e str es s a nd ap op to si s A ct iv at es N rf -2 a nd u pr eg u- la te s H O -1 e xp re ss io n It en ha nc es a nt io xi da nt de fe ns e, re du ce s R O S, a nd pr ot ec ts c el ls fr om h yp ox ia - in du ce d ap op to si s BV 2 m ic ro gl ia l c el ls u nd er hy po xi a in du ce d by C oC l₂ EG C G tr ea tm en t i nc re as ed N rf 2 an d H O -1 e xp re ss io n in C oC l₂- tre at ed B V 2 ce lls , at te nu at in g ox id at iv e str es s an d pr ev en tin g ap op to si s [1 83 ] TL R 4- M yD 88 -N F- κB M ed ia te s i nfl am m at or y re sp on se s; tr ig ge rs th e re le as e of p ro -in fla m m at or y cy to ki ne s B lo ck s T LR 4- M yD 88 -N F- κB si gn al in g, re du ci ng T N F- α, IL -1 β, a nd IL -6 le ve ls Su pp re ss es in fla m m at io n an d pr ot ec ts a ga in st tis su e da m - ag e, p ot en tia lly re du ci ng tu m or -p ro m ot in g in fla m - m at io n M ou se m od el o f a cu te Ps eu do m on as a er ug in os a pn eu m on ia M al e m ic e w er e pr e- tre at ed w ith E G C G (2 0, 4 0, a nd 80 m g/ kg ) f or 3 d ay s be fo re in fe ct io n w ith Ps eu do m on as a er ug in os a. EG C G re du ce d se ru m A LT /A ST le ve ls a nd cy to ki ne e xp re ss io n [1 84 ] ER α3 6 Is of or m o f e str og en re ce pt or al ph a in vo lv ed in c an ce r pr og re ss io n an d ch em or e- si st an ce EG C G ta rg et s E R α3 6, in hi b- iti ng it s e xp re ss io n In hi bi ts H C C c el l p ro lif er a- tio n, in du ce s a po pt os is , a nd in hi bi ts tu m or g ro w th H ep 3B (H C C c el l l in e) , M ic e In v itr o ce ll vi ab ili ty , a po p- to si s a ss ay s, an d in v iv o tu m or x en og ra ft m od el in nu de m ic e [1 85 ] M A PK /E R K Re gu la te s c el l g ro w th , d if- fe re nt ia tio n, su rv iv al , a nd re sp on se to st re ss ; i nv ol ve d in M M P- 1 ac tiv at io n le ad - in g to c ol la ge n de gr ad at io n Su pp re ss ed T N F- α- in du ce d M M P- 1 ex pr es si on a nd se cr et io n; re du ce d ph os - ph or yl at io n of E R K b ut n ot JN K o r p 38 . S up pr es se d ph os ph or yl at io n of M EK an d Sr c, u ps tre am re gu la - to rs o f E R K Re du ce d co lla ge n br ea k- do w n, d ec re as ed sk in a gi ng sy m pt om s l ik e w rin kl es a nd lo ss o f e la sti ci ty b y in hi bi t- in g M M P- 1 H s6 8 hu m an d er m al fi br o- bl as t c el ls EG C G a t 1 0 μM a nd 2 0 μM pr e- tre at m en t i nh ib ite d TN F- α- in du ce d M M P- 1 ex pr es si on a nd se cr et io n. Re du ce d ph os ph or yl at io n of E R K , M EK , a nd S rc w as o bs er ve d. A nt i-a gi ng eff ec ts d em on str at ed v ia su pp re ss io n of M M P- 1 ac tiv ity li nk ed to re du ce d RO S an d pr o- in fla m m at or y cy to ki ne s [1 86 ] JA K /S TA T M ed ia te s c yt ok in e si gn al in g an d co nt ro ls c el l p ro lif er a- tio n, d iff er en tia tio n, a nd ap op to si s In hi bi ts JA K /S TA T si gn al in g by re du ci ng S TA T3 p ho s- ph or yl at io n Su pp re ss es tu m or p ro gr es - si on a nd re du ce s c he m or e- si st an ce H ep G 2 liv er c an ce r c el ls EG C G in hi bi te d IL -6 -in - du ce d ST A T3 a ct iv at io n, re du ci ng tu m or p ro gr es si on an d ch em or es ist an ce [1 87 ] W nt /β -c at en in Re gu la te s c el l f at e de te r- m in at io n, m ig ra tio n, a nd pr ol ife ra tio n Su pp re ss es β -c at en in a cc u- m ul at io n an d W nt si gn al in g In hi bi ts c el l m ig ra tio n, in va - si on , a nd p ro lif er at io n H C T1 16 c ol on c an ce r c el ls EG C G d ec re as ed n uc le ar β- ca te ni n le ve ls a nd in hi bi te d W nt ta rg et g en e ex pr es si on [1 88 ] AAPS PharmSciTech (2025) 26:137 137 Page 16 of 30 This stark contrast underlines the enzymatic vulnerability
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