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Review

Plant-Derived Nanomaterials and Protein Misfolding Disorders: Green Production Approaches, Biological Interactions, and Research Trends (2015–2025)

by
Corina Dalia Toderescu
1,
Iulia Cresneac
1,*,
Alexandru Oancea
2,*,
Svetlana Trifunschi
1,
Melania Florina Munteanu
1 and
Casiana Boru
2
1
Faculty of Pharmacy, “Vasile Goldis” Western University of Arad, 310048 Arad, Romania
2
Faculty of Medicines, “Vasile Goldis” Western University of Arad, 310048 Arad, Romania
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2026, 16(5), 2620; https://doi.org/10.3390/app16052620
Submission received: 28 January 2026 / Revised: 25 February 2026 / Accepted: 4 March 2026 / Published: 9 March 2026
(This article belongs to the Special Issue Green Synthesis of Plant-Based Nanoparticles: Influence of Physicochemical Factors on Formation and Stability)
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Abstract

Protein misfolding and aggregation represent key pathological mechanisms in neurodegenerative and systemic amyloid disorders, yet disease-modifying therapeutic strategies remain limited. In recent years, plant-derived nanomaterials have attracted increasing attention as multifunctional platforms capable of interacting with misfolded proteins and modulating aggregation-related pathways. This review examines the evolution of research between 2015 and 2025 on plant-derived nanomaterials—including green-synthesized metallic nanoparticles, plant extracellular vesicles, and phytochemical-based nano-delivery systems—in the context of protein misfolding disorders. The available literature was analyzed to identify principal mechanisms of action, experimental models, and emerging therapeutic perspectives. Current evidence suggests that these nanomaterials may influence protein aggregation through direct molecular interactions, modulation of oxidative stress and neuroinflammatory responses, and enhancement of cellular protein clearance processes. However, the field remains characterized by methodological heterogeneity, limited standardization, and insufficient translational validation. By synthesizing recent developments, this review highlights key research trends, mechanistic gaps, and future directions necessary for advancing plant-derived nanomaterials toward biomedical applications targeting protein misfolding diseases.

1. Introduction

Protein misfolding and aggregation into amyloid fibrils represent central pathogenic mechanisms in numerous human disorders, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, as well as systemic amyloidoses [1,2,3,4,5,6]. The accumulation of misfolded proteins disrupts cellular homeostasis, impairs proteostasis networks, and contributes to progressive tissue dysfunction. Despite extensive research, disease-modifying therapies targeting protein aggregation remain limited, and most currently available treatments primarily address symptoms rather than underlying pathogenic processes [5,7,8].
Nanotechnology has emerged as a promising platform for addressing complex biological challenges associated with protein misfolding [4,8,9,10]. Nanomaterials can interact with biomolecules at multiple levels, enabling modulation of aggregation pathways, targeted delivery of bioactive compounds, and engagement with cellular stress responses. However, conventional nanomedicine approaches often rely on synthetic materials, which may present challenges related to biocompatibility, long-term safety, and translational scalability.
Within this context, plant-derived nanomaterials—including green-synthesized metallic nanoparticles, plant extracellular nanovesicles, and nanoparticle-based delivery systems for phytochemicals—have gained increasing attention [9,10,11,12]. These systems combine nanoscale functionality with the intrinsic bioactivity of plant-derived compounds, offering multifunctional properties such as antioxidant activity, anti-inflammatory potential, and capacity to influence proteostasis-related pathways. Their natural origin and potential for eco-friendly synthesis further distinguish them from purely synthetic nanomaterials.
Although a growing number of studies have explored plant-derived nanomaterials in neurodegenerative and protein misfolding contexts, the literature remains heterogeneous, with varying experimental models, methodological approaches, and levels of mechanistic detail [13,14]. Existing reports often emphasize neuroprotective outcomes without systematically examining their direct impact on aggregation processes. Consequently, an integrated synthesis of current evidence, mechanisms, and research gaps is needed to clarify the role of plant-derived nanomaterials in modulating protein misfolding.
The present review examines the evolution of research between 2015 and 2025 on plant-derived nanomaterials and their relevance to protein misfolding disorders. The objectives are to synthesize current knowledge, classify major categories of plant-derived nanomaterials, analyze reported mechanisms of action, and identify methodological limitations and translational challenges. By integrating findings across disciplines, this review aims to provide a structured perspective on the potential and current maturity of plant-derived nanomaterials as emerging tools for addressing protein misfolding pathology.
In this review, the term plant-derived nanomaterials also encompasses nanoparticle systems that incorporate plant-origin bioactive compounds as therapeutic payloads. Although the nanocarrier itself may be synthetic, its functional activity is directly linked to plant-derived molecules that modulate protein misfolding pathways. This classification reflects the translational strategy of integrating plant bioactives with nanoscale delivery systems.

2. Literature Survey and Scope

Literature Search: A structured literature search was conducted using major scientific databases, including PubMed, Web of Science, and Scopus, covering publications from 2015 to 2025 [15,16,17]. Search queries combined keywords related to plant-derived nanomaterials and protein misfolding, such as “plant-derived nanoparticles”, “green-synthesized nanoparticles”, “plant extracellular vesicles”, “protein misfolding”, “amyloid aggregation”, and “neurodegenerative diseases”. Reference lists of relevant articles and reviews were additionally screened to ensure comprehensive coverage of pertinent studies.
Scope and Selection Criteria: This review includes original experimental studies (in vitro and in vivo) as well as relevant review articles published within the defined timeframe. Studies were considered eligible if they met the following criteria: (1) involvement of nanomaterials derived from plant sources, including green-synthesized metallic nanoparticles or plant extracellular nanovesicles; and (2) evaluation of their effects on protein misfolding, aggregation, or amyloid-related processes, either through direct aggregation measurements or related biological outcomes in disease models. Studies outside this thematic scope were excluded.
Screening and Data Extraction: Relevant publications were identified through an initial screening of titles and abstracts, followed by full-text assessment. From each included study, key information was extracted, including nanomaterial type and plant source, targeted protein or aggregation model, experimental system, and reported outcomes related to protein aggregation or associated pathological markers. Particular attention was given to whether aggregation kinetics were directly assessed or inferred from secondary biological endpoints [18].
Quality Consideration: Although a formal systematic bias assessment was not conducted, the methodological rigor of included studies was qualitatively evaluated. Criteria included nanoparticle characterization, experimental design, presence of controls, quantitative analysis, and relevance of biological models.
Temporal Framework: To identify research trends, the literature was analyzed across three time intervals (2015–2017, 2018–2020, and 2021–2025), allowing examination of the progression from exploratory investigations to more targeted and mechanistic studies.
To enhance transparency of the literature selection process, a PRISMA-style flow diagram summarizing study identification, screening, eligibility assessment, and inclusion was prepared (Figure 1).
In addition, a structured table describing the characteristics of the experimental studies included in the qualitative synthesis was developed and is presented in the Section 3.
PRISMA-style flow diagram is illustrating the identification, screening, eligibility assessment, and inclusion of experimental studies evaluating plant-derived nanomaterials in protein misfolding and aggregation research (2015–2025).

3. Results

3.1. Foundational Background (Pre-2015)

Prior to 2015, several mechanistic studies demonstrated that nanoparticle surface chemistry, size, and interface properties could modulate amyloid nucleation, fibril elongation, and protein stability in simplified aggregation systems. These foundational observations established the conceptual framework for later investigations and informed the transition toward biocompatible and plant-derived nanomaterials in the post-2015 period [19,20,21,22].

3.2. Early Studies Primarily Explored Conceptual and Proof-of-Principle Aspects

2015–2017—Early Concepts and Preliminary Studies: Between 2015 and 2017, research addressing nanoparticle-mediated modulation of protein misfolding was primarily exploratory and concept-driven. Most investigations focused on inorganic or synthetic nanomaterials evaluated in in vitro aggregation models, particularly targeting amyloid-β and α-synuclein fibrillation pathways [23,24]. These studies examined nanoparticle–protein interactions, surface chemistry effects, and the capacity of nanoscale systems to influence aggregation kinetics [25,26]. In contrast, plant-derived nanomaterials were only sporadically investigated during this period, and their biological activity was largely inferred from broader nanomedicine research rather than directly demonstrated [24]. Methodological limitations, including simplified experimental models and limited mechanistic characterization, constrained translational interpretation. Nevertheless, this stage established the conceptual basis for subsequent research exploring plant-based nanomaterials as modulators of protein misfolding processes [24,26].
2018–2020—Emergence of Green-Synthesized Nanoparticles in Neurodegeneration: From the late 2010s onward, research on plant-mediated nanomaterial production expanded significantly, driven by the need for biocompatible and environmentally sustainable approaches. Studies during this period predominantly investigated green-synthesized metallic nanoparticles generated using plant extracts rich in polyphenols and reducing phytochemicals [27,28]. These nanomaterials were primarily evaluated in experimental models of neurodegeneration, with emphasis on oxidative stress modulation, anti-inflammatory activity, and cytoprotective effects [27,29,30].
Most investigations assessed downstream biological outcomes, including neuronal viability, reduction of reactive oxygen species, and modulation of inflammatory signaling pathways, rather than directly quantifying protein aggregation kinetics. Neuroprotective effects were frequently reported in in vitro and in vivo models of Alzheimer’s and Parkinson’s diseases; however, mechanistic links to amyloid fibrillation or protein misfolding pathways were often indirect [31,32]. Surface-bound phytochemicals and redox-active coatings were proposed as contributing factors to biological activity, yet detailed characterization of nanoparticle–protein interactions remained limited [33,34].
Overall, this phase marked the transition from conventional nanomedicine approaches toward plant-derived nanomaterials as potential modulators of neurodegenerative processes. However, experimental designs were frequently centered on general neuroprotection rather than explicit evaluation of aggregation inhibition, leaving a gap between observed biological outcomes and direct evidence of protein misfolding modulation.
2021–2025—Expansion to Plant Nanovesicles and Direct Anti-Amyloid Applications: Between 2021 and 2025, the literature on plant-derived nanomaterials and protein misfolding expanded substantially, reflecting a transition from exploratory research to more targeted investigations [11,13,14]. Two major directions became evident during this period. First, an increasing number of integrative reviews synthesized existing knowledge on green-synthesized nanomaterials and plant-based bioactive compounds, indicating consolidation of the field and recognition of its therapeutic relevance [13,14]. Second, experimental studies increasingly examined plant-derived extracellular vesicles and phytochemical-capped nanoparticles as active modulators of neurodegenerative processes [11,35].
Plant-derived nanovesicles attracted particular attention due to their intrinsic bioactivity, capacity to transport molecular cargos, and potential to influence proteostasis-related pathways. Studies evaluated their roles in neuronal protection, modulation of inflammatory responses, and regulation of cellular stress mechanisms, suggesting a broader biological function beyond conventional drug delivery systems [27,29,31]. At the same time, selected experimental investigations began to directly address protein aggregation, demonstrating that plant-derived nanomaterials could interfere with fibrillation processes of aggregation-prone proteins under controlled conditions [36,37].
Despite these advances, explicitly integrative studies combining plant-derived nanomaterials with quantitative protein misfolding assays remained relatively limited. Most investigations continued to prioritize downstream biological outcomes, such as neuroprotection and behavioral improvement, rather than direct measurement of aggregation kinetics. Nevertheless, the period marked a clear shift toward mechanistic exploration of nanoparticle–protein interactions and growing recognition of plant-derived nanomaterials as potential modulators of protein misfolding pathology [37,38].
Summary of Trend: Over the past decade, research on plant-derived nanomaterials in the context of protein misfolding has progressed from conceptual exploration to more structured experimental investigation [13]. Early studies were primarily limited to proof-of-concept demonstrations and indirect neuroprotective assessments, whereas more recent work increasingly incorporates mechanistic analyses and targeted aggregation models. The growing number of publications reflects an expanding interdisciplinary interest integrating nanotechnology, phytochemistry, and neurodegenerative disease research [37,38].
Despite this progression, the field remains characterized by methodological heterogeneity, limited standardization of nanoparticle characterization, and a relatively small number of studies directly quantifying aggregation kinetics [27,28]. Many investigations continue to emphasize downstream biological outcomes rather than explicit evaluation of protein misfolding processes. Consequently, a gap persists between the theoretical potential of plant-derived nanomaterials and the experimental evidence supporting their direct role in modulating protein aggregation. This gap underpins the need for more integrative and mechanistically oriented research, as explored in the following sections.

3.3. Categories of Plant-Derived Nanoparticles and Key Studies

Research over the past decade has identified several distinct categories of plant-derived nanomaterials relevant to protein misfolding disorders, each characterized by specific mechanisms of action, experimental applications, and translational potential.

3.3.1. Green-Synthesized Metallic Nanomaterials

Green-synthesized metallic nanoparticles represent one of the most extensively investigated categories. These systems are produced using plant extracts rich in phytochemicals that act as both reducing and stabilizing agents, resulting in nanoscale structures with bioactive surface coronas [9,10,39]. Experimental studies have primarily evaluated their antioxidant, anti-inflammatory, and cytoprotective properties in cellular and animal models of neurodegeneration [27,32]. In selected cases, these nanomaterials were shown to influence protein aggregation pathways, potentially through surface-mediated interactions, modulation of oxidative stress, or stabilization of native protein conformations [36,40]. However, many investigations attribute observed effects to general neuroprotective mechanisms rather than direct molecular binding to misfolded proteins, highlighting the need for more detailed mechanistic characterization [38]. Despite extensive investigation, the specific contribution of metallic cores versus phytochemical surface coronas remains insufficiently delineated, and comparative studies directly assessing nanoparticle–protein binding mechanisms are still scarce [24,27].

3.3.2. Plant-Derived Extracellular Nanovesicles

Plant extracellular vesicles and exosome-like nanovesicles constitute an emerging category with distinct biological properties [11,12,35]. These nanoscale lipid vesicles carry plant-derived proteins, metabolites, lipids, and regulatory RNAs, enabling interspecies molecular communication and cellular uptake in mammalian systems [11,35,41]. Research has increasingly explored their role in neuroinflammatory modulation, cellular stress responses, and proteostasis-related pathways [31,35]. Although direct evidence of aggregation inhibition remains limited, their capacity to transport bioactive cargo and influence intracellular signaling suggests potential relevance for protein misfolding disorders [11,35]. This area remains at an early stage, with ongoing efforts focused on vesicle characterization, biodistribution, and mechanistic interaction with neural cells. Compared with metallic nanoparticles, plant-derived nanovesicles offer intrinsic biological functionality but present greater methodological variability in isolation and characterization, complicating cross-study comparability and mechanistic interpretation [11,35,37].

3.3.3. Nano-Formulations of Plant-Derived Bioactive Compounds

A complementary strategy involves the incorporation of plant-derived anti-amyloidogenic compounds into nanoparticle delivery systems [40,42,43]. Polyphenols and other phytochemicals with known aggregation-inhibiting properties have been formulated into polymeric nanoparticles, liposomes, and nanoemulsions to enhance stability, bioavailability, and brain targeting [27,32,36]. These systems primarily function as delivery platforms rather than active nanomaterials themselves, facilitating the transport of bioactive molecules to sites of protein aggregation [27,32]. Studies have demonstrated improved pharmacokinetics, enhanced brain penetration, and increased efficacy in experimental models compared with free compounds [26,27,44]. However, distinguishing the therapeutic contribution of the carrier from that of the encapsulated phytochemical remains a key methodological challenge [21,45]. The inclusion of phytochemical-loaded nanoparticle systems within the scope of plant-derived nanomaterials is justified by their functional dependence on plant-origin bioactive compounds, which drive aggregation-modulating activity even when the carrier itself is synthetic [30,36,38].

3.3.4. Integrative Perspective

Collectively, these categories illustrate the diverse strategies through which plant-derived nanomaterials may influence protein misfolding, ranging from direct nanoparticle–protein interactions to delivery-mediated modulation of cellular pathways [24]. Despite promising findings, the field remains characterized by heterogeneity in experimental design, limited standardization of nanoparticle characterization, and relatively few studies directly quantifying aggregation kinetics [21,22]. These limitations underscore the need for integrative research approaches combining nanomaterial engineering, protein biophysics, and disease modeling.

3.3.5. Study Selection and Characteristics of Included Studies

The structured literature search identified experimental studies evaluating plant-derived nanomaterials in protein misfolding and aggregation contexts. After screening and eligibility assessment, experimental studies were included in the qualitative synthesis. Their key characteristics are summarized in Table 1, including nanomaterial type, plant source, physicochemical characterization, target proteins or disease models, experimental systems, aggregation endpoints (direct versus indirect), and principal outcomes.
The table summarizes experimental studies identified through the structured literature search, including nanomaterial type, plant source, characterization parameters, target proteins, experimental systems, aggregation endpoints (direct vs indirect), and main outcomes.

3.3.6. Assessment of Aggregation: Direct vs Indirect Evidence

Analysis of the included experimental studies revealed two principal categories of evidence regarding aggregation modulation. A subset of studies directly evaluated aggregation kinetics or fibril formation using biophysical and biochemical assays, while others inferred anti-aggregation effects through downstream biological outcomes such as oxidative stress reduction, anti-inflammatory responses, cellular viability, or behavioral improvements in animal models. Both evidence types contribute to understanding the potential role of plant-derived nanomaterials in modulating protein misfolding, although direct aggregation measurements remain comparatively less frequent (Table 2).

3.4. Effects of Plant-Derived Nanoparticles on Protein Misfolding and Aggregation

This section synthesizes current evidence regarding the capacity of plant-derived nanomaterials to influence protein misfolding processes, distinguishing between direct molecular effects on aggregation pathways and indirect modulation through cellular mechanisms [21,30,38].

3.4.1. Direct Modulation of Aggregation Pathways

A growing body of experimental work indicates that plant-derived nanomaterials can directly interfere with protein aggregation kinetics [40,42,66,67,68]. These effects are typically mediated by nanoparticle–protein interactions, including multivalent binding, surface-mediated stabilization of native conformations, or redirection of aggregation toward non-toxic off-pathway species [21,22]. Polyphenol-functionalized nanomaterials, in particular, have demonstrated enhanced aggregation-inhibiting activity compared with free compounds, suggesting that nanoscale presentation increases local concentration and binding efficiency [36]. Despite these findings, quantitative mechanistic studies remain relatively limited, and the molecular determinants of nanoparticle–protein interactions are not yet fully characterized [22].

3.4.2. Indirect Modulation via Cellular Pathways

In addition to direct molecular interactions, plant-derived nanomaterials frequently influence protein misfolding indirectly by altering the cellular environment. Experimental studies report reductions in oxidative stress, modulation of inflammatory signaling, and enhancement of cellular protein clearance mechanisms following nanoparticle exposure. These effects may collectively reduce conditions that favor protein misfolding and aggregation. Activation of autophagy, improved proteasomal activity, and regulation of neuroinflammatory responses have all been proposed as contributing pathways [31,32,69]. However, most studies measure downstream biological endpoints rather than direct changes in aggregation kinetics, making causal links to protein misfolding modulation difficult to establish [21,38].

3.4.3. Strength of Evidence and Current Limitations

Overall, available evidence suggests that plant-derived nanomaterials can influence protein misfolding through multiple complementary mechanisms. Nevertheless, the field remains constrained by limited standardization of aggregation assays, heterogeneity in nanoparticle characterization, and a relatively small number of studies using aggregation kinetics as a primary outcome [21]. Many investigations emphasize general neuroprotective effects, while direct quantification of fibril formation or clearance remains comparatively rare [32,38]. These limitations highlight the need for integrative experimental designs combining protein biophysics, nanomaterial characterization, and disease-relevant models [23,26].

3.5. Emerging Limitations and Future Perspectives

The literature published between 2015 and 2025 reveals several recurring methodological, mechanistic, and translational challenges that currently limit the advancement of plant-derived nanomaterials in protein misfolding research.

3.5.1. Methodological Standardization

Significant variability exists in nanoparticle synthesis protocols, plant sources, and physicochemical characterization methods. Differences in particle size, morphology, surface chemistry, and phytochemical coatings complicate cross-study comparisons and reproducibility. Standardized reporting frameworks and characterization criteria remain insufficiently implemented, particularly for plant-derived extracellular vesicles, where isolation procedures and purity assessments vary considerably [24,27,35].

3.5.2. Limited Direct Assessment of Aggregation Processes

A substantial proportion of studies infer anti-aggregation activity from secondary biological outcomes rather than directly measuring protein aggregation kinetics. Quantitative analyses of nucleation dynamics, fibril morphology, oligomer formation, and aggregate clearance remain relatively underrepresented, creating a gap between observed biological effects and mechanistic understanding [4,18].

3.5.3. Biological Model Constraints

Most investigations rely on simplified in vitro systems or short-term cellular models. Fewer studies employ disease-relevant in vivo models capable of evaluating biodistribution, pharmacokinetics, immune responses, and long-term safety of plant-derived nanomaterials. The in vivo behavior of plant nanovesicles, including organ targeting, circulation time, and clearance pathways, remains insufficiently characterized [70].

3.5.4. Mechanistic Uncertainties

The molecular basis of nanoparticle–protein interactions remains incompletely defined. While surface-mediated binding and sequestration mechanisms have been proposed, their relevance in complex biological environments is unclear due to protein corona formation and competing endogenous interactions. Similarly, the intracellular mechanisms by which plant-derived nanovesicles influence proteostasis pathways require further investigation [71].

3.5.5. Translational and Manufacturing Challenges

Scaling plant-based nanoparticle production while maintaining consistency, purity, and stability presents practical challenges. Regulatory requirements, toxicological evaluation, batch variability, and long-term storage stability remain critical considerations for future therapeutic development [24,27,44].
Collectively, these limitations highlight the need for standardized experimental frameworks, quantitative aggregation assays, disease-relevant biological models, and mechanistic investigations. Addressing these challenges will be essential for translating plant-derived nanomaterials from exploratory research toward clinically relevant strategies targeting protein misfolding disorders.

4. Discussion

The present overview highlights the evolving role of plant-derived nanomaterials as potential modulators of protein misfolding processes within neurodegenerative and systemic amyloid disorders. While early research primarily demonstrated proof-of-concept neuroprotective effects, recent studies increasingly address mechanistic interactions and targeted modulation of aggregation pathways [72,73].

4.1. Interpretation of Current Evidence

Available findings indicate that plant-derived nanomaterials exert both direct and indirect influences on protein misfolding. Direct mechanisms involve nanoparticle–protein interactions capable of altering aggregation kinetics, stabilizing native conformations, or redirecting aggregation toward less toxic species [74,75]. Indirect effects arise through modulation of oxidative stress, neuroinflammation, and cellular proteostasis pathways [76]. However, these mechanisms are not consistently investigated within the same experimental frameworks, resulting in fragmented evidence [8,77,78].

4.2. Comparison with Conventional Therapeutic Approaches

Compared with conventional small-molecule therapeutics, plant-derived nanomaterials offer multifunctional properties, including multivalent interactions, enhanced delivery of bioactive compounds, and potential engagement with multiple pathogenic pathways simultaneously. Their biocompatibility and natural origin represent additional advantages, particularly in the context of chronic neurodegenerative diseases. Nevertheless, unlike established pharmacological strategies, nanoparticle-based approaches remain largely preclinical and require further validation in disease-relevant models [79,80].

4.3. Mechanistic Integration

The dual capacity of plant-derived nanomaterials to interact directly with aggregation-prone proteins and indirectly modulate cellular pathways suggests a multifactorial mode of action. The relative contribution of these mechanisms likely varies depending on nanoparticle composition, surface chemistry, and biological context [81,82]. Integrative experimental designs capable of distinguishing molecular binding effects from cellular modulation are needed to clarify these relationships [83].

4.4. Translational Considerations

Despite promising experimental findings, translational progress remains limited. Challenges include variability in synthesis protocols, incomplete understanding of nanoparticle biodistribution, insufficient long-term safety data, and regulatory complexities associated with biologically derived materials [72,84,85]. Addressing these issues will be essential for advancing plant-derived nanomaterials from exploratory research toward clinical application [36,86].
These complementary mechanisms and translational considerations are schematically summarized in Figure 2.
Direct mechanisms include nanoparticle–protein interactions affecting nucleation and aggregation pathways, while indirect effects involve modulation of oxidative stress, neuroinflammation, and proteostasis. The scheme also highlights key translational requirements such as standardized characterization, reproducible green synthesis, pharmacokinetic evaluation, and methodological harmonization.

4.5. Translational Readiness and Research Priorities

Advancing plant-derived nanomaterials toward clinical application requires addressing several translational and methodological priorities. Standardization of nanoparticle characterization remains a critical need, as variability in size, morphology, surface chemistry, and phytochemical composition complicates reproducibility and cross-study comparison [87]. Similarly, reproducibility and scalability of green synthesis present challenges due to biological variability in plant sources and extraction conditions.
Systematic investigation of pharmacokinetics, biodistribution, immune responses, and long-term safety remains limited, particularly for metallic nanoparticles and plant-derived nanovesicles. Establishing harmonized methodological frameworks for vesicle isolation, characterization, and functional validation—similar to existing extracellular vesicle research guidelines—would substantially improve transparency and comparability [88,89,90].
Finally, strengthening the link between nanoparticle–protein interactions and disease-relevant outcomes represents an essential step. Integrative experimental designs combining aggregation kinetics, structural characterization, and in vivo validation are necessary to support the translational development of plant-derived nanomaterials for protein misfolding disorders [91].

5. Conclusions

This overview highlights that, between 2015 and 2025, experimental investigations of plant-derived nanomaterials in the context of protein misfolding have increasingly focused on neurodegenerative disease-related proteins, particularly amyloid-β and α-synuclein. Analysis of the included studies indicates that most evidence derives from in vitro aggregation models, while comparatively fewer investigations incorporate in vivo validation.
The reviewed studies demonstrate two principal patterns of aggregation modulation: a subset directly quantified fibrillation kinetics or structural aggregation endpoints, whereas a substantial proportion inferred anti-aggregation effects through downstream biological outcomes such as oxidative stress attenuation, anti-inflammatory activity, or behavioral improvements in animal models. Although physicochemical characterization of nanoparticles was generally reported, variability in aggregation assays and model selection limits cross-study comparability.
Overall, the current body of evidence supports the potential of plant-derived nanomaterials as multifunctional modulators of protein aggregation; however, the field remains methodologically heterogeneous and predominantly preclinical. Greater standardization of nanoparticle characterization, direct kinetic assessment of aggregation, and integration of disease-relevant in vivo models will be necessary to clarify mechanistic pathways and assess translational feasibility.

Author Contributions

Conceptualization, C.D.T. and M.F.M.; methodology, I.C.; software, not applicable; validation, C.D.T., M.F.M. and I.C.; formal analysis, I.C.; investigation, I.C.; resources, C.D.T. and M.F.M.; data curation, I.C.; writing—original draft preparation, I.C.; writing—review and editing, C.D.T., M.F.M., A.O., S.T. and C.B.; visualization, I.C.; supervision, M.F.M.; project administration, C.D.T. and M.F.M.; funding acquisition, not applicable. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Soto, C. Unfolding the Role of Protein Misfolding in Neurodegenerative Diseases. Nat. Rev. Neurosci. 2003, 4, 49–60. [Google Scholar] [CrossRef]
  2. Dobson, C.M. Protein Folding and Misfolding. Nature 2003, 426, 884–890. [Google Scholar] [CrossRef]
  3. Chiti, F.; Dobson, C.M. Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. Annu. Rev. Biochem. 2017, 86, 27–68. [Google Scholar] [CrossRef]
  4. Knowles, T.P.J.; Vendruscolo, M.; Dobson, C.M. The Amyloid State and Its Association with Protein Misfolding Diseases. Nat. Rev. Mol. Cell Biol. 2014, 15, 384–396. [Google Scholar] [CrossRef]
  5. Selkoe, D.J.; Hardy, J. The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years. EMBO Mol. Med. 2016, 8, 595–608. [Google Scholar] [CrossRef] [PubMed]
  6. Eisenberg, D.; Jucker, M. The Amyloid State of Proteins in Human Diseases. Cell 2012, 148, 1188–1203. [Google Scholar] [CrossRef] [PubMed]
  7. Kepp, K.P. Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease. J. Alzheimers Dis. 2017, 55, 447–457. [Google Scholar] [CrossRef]
  8. Nixon, R.A. The Role of Autophagy in Neurodegenerative Disease. Nat. Med. 2013, 19, 983–997. [Google Scholar] [CrossRef]
  9. Iravani, S. Green Synthesis of Metal Nanoparticles Using Plants. Green Chem. 2011, 13, 2638. [Google Scholar] [CrossRef]
  10. Mittal, A.K.; Chisti, Y.; Banerjee, U.C. Synthesis of Metallic Nanoparticles Using Plant Extracts. Biotechnol. Adv. 2013, 31, 346–356. [Google Scholar] [CrossRef] [PubMed]
  11. Dad, H.A.; Gu, T.-W.; Zhu, A.-Q.; Huang, L.-Q.; Peng, L.-H. Plant Exosome-like Nanovesicles: Emerging Therapeutics and Drug Delivery Nanoplatforms. Mol. Ther. J. Am. Soc. Gene Ther. 2021, 29, 13–31. [Google Scholar] [CrossRef] [PubMed]
  12. Zhang, M.; Viennois, E.; Prasad, M.; Zhang, Y.; Wang, L.; Zhang, Z.; Han, M.K.; Xiao, B.; Xu, C.; Srinivasan, S.; et al. Edible Ginger-Derived Nanoparticles: A Novel Therapeutic Approach for the Prevention and Treatment of Inflammatory Bowel Disease and Colitis-Associated Cancer. Biomaterials 2016, 101, 321–340. [Google Scholar] [CrossRef] [PubMed]
  13. Izadi, R.; Bahramikia, S.; Akbari, V. Green Synthesis of Nanoparticles Using Medicinal Plants as an Eco-Friendly and Therapeutic Potential Approach for Neurodegenerative Diseases: A Comprehensive Review. Front. Neurosci. 2024, 18, 1453499. [Google Scholar] [CrossRef] [PubMed]
  14. Zhytniakivska, O.; Chaturvedi, T.; Thomsen, M.H. Plant-Based Inhibitors of Protein Aggregation. Biomolecules 2025, 15, 481. [Google Scholar] [CrossRef]
  15. National Library of Medicine PubMed. Available online: https://www.nlm.nih.gov/ (accessed on 27 January 2026).
  16. Clarivate Analytics Web of Science. Available online: https://clarivate.com/academia-government/scientific-and-academic-research/research-discovery-and-referencing/web-of-science/ (accessed on 27 January 2026).
  17. Scopus. Available online: https://www.elsevier.com/en-au/products/scopus (accessed on 27 January 2026).
  18. Cohen, S.I.A.; Linse, S.; Luheshi, L.M.; Hellstrand, E.; White, D.A.; Rajah, L.; Otzen, D.E.; Vendruscolo, M.; Dobson, C.M.; Knowles, T.P.J. Proliferation of Amyloid-Β42 Aggregates Occurs through a Secondary Nucleation Mechanism. Proc. Natl. Acad. Sci. USA 2013, 110, 9758–9763. [Google Scholar] [CrossRef]
  19. Linse, S.; Cabaleiro-Lago, C.; Xue, W.-F.; Lynch, I.; Lindman, S.; Thulin, E.; Radford, S.E.; Dawson, K.A. Nucleation of Protein Fibrillation by Nanoparticles. Proc. Natl. Acad. Sci. USA 2007, 104, 8691–8696. [Google Scholar] [CrossRef]
  20. Cabaleiro-Lago, C.; Quinlan-Pluck, F.; Lynch, I.; Lindman, S.; Minogue, A.M.; Thulin, E.; Walsh, D.M.; Dawson, K.A.; Linse, S. Inhibition of Amyloid Beta Protein Fibrillation by Polymeric Nanoparticles. J. Am. Chem. Soc. 2008, 130, 15437–15443. [Google Scholar] [CrossRef]
  21. Mahmoudi, M.; Lynch, I.; Ejtehadi, M.R.; Monopoli, M.P.; Bombelli, F.B.; Laurent, S. Protein-Nanoparticle Interactions: Opportunities and Challenges. Chem. Rev. 2011, 111, 5610–5637. [Google Scholar] [CrossRef]
  22. Monopoli, M.P.; Aberg, C.; Salvati, A.; Dawson, K.A. Biomolecular Coronas Provide the Biological Identity of Nanosized Materials. Nat. Nanotechnol. 2012, 7, 779–786. [Google Scholar] [CrossRef]
  23. John, T.; Gladytz, A.; Kubeil, C.; Martin, L.L.; Risselada, H.J.; Abel, B. Impact of Nanoparticles on Amyloid Peptide and Protein Aggregation: A Review with a Focus on Gold Nanoparticles. Nanoscale 2018, 10, 20894–20913. [Google Scholar] [CrossRef]
  24. Pelaz, B.; Alexiou, C.; Alvarez-Puebla, R.A.; Alves, F.; Andrews, A.M.; Ashraf, S.; Balogh, L.P.; Ballerini, L.; Bestetti, A.; Brendel, C.; et al. Diverse Applications of Nanomedicine. ACS Nano 2017, 11, 2313–2381. [Google Scholar] [CrossRef]
  25. Corbo, C.; Molinaro, R.; Parodi, A.; Toledano Furman, N.E.; Salvatore, F.; Tasciotti, E. The Impact of Nanoparticle Protein Corona on Cytotoxicity, Immunotoxicity and Target Drug Delivery. Nanomedicine 2016, 11, 81–100. [Google Scholar] [CrossRef] [PubMed]
  26. Blanco, E.; Shen, H.; Ferrari, M. Principles of Nanoparticle Design for Overcoming Biological Barriers to Drug Delivery. Nat. Biotechnol. 2015, 33, 941–951. [Google Scholar] [CrossRef] [PubMed]
  27. Patra, J.K.; Das, G.; Fraceto, L.F.; Campos, E.V.R.; Rodriguez-Torres, M.D.P.; Acosta-Torres, L.S.; Diaz-Torres, L.A.; Grillo, R.; Swamy, M.K.; Sharma, S.; et al. Nano Based Drug Delivery Systems: Recent Developments and Future Prospects. J. Nanobiotechnol. 2018, 16, 71. [Google Scholar] [CrossRef]
  28. Sharma, D.; Kanchi, S.; Bisetty, K. Biogenic Synthesis of Nanoparticles: A Review. Arab. J. Chem. 2019, 12, 3576–3600. [Google Scholar] [CrossRef]
  29. Spillantini, M.G.; Goedert, M. Neurodegeneration and the Ordered Assembly of α-Synuclein. Cell Tissue Res. 2018, 373, 137–148. [Google Scholar] [CrossRef]
  30. Dhouafli, Z.; Cuanalo-Contreras, K.; Hayouni, E.A.; Mays, C.E.; Soto, C.; Moreno-Gonzalez, I. Inhibition of Protein Misfolding and Aggregation by Natural Phenolic Compounds. Cell. Mol. Life Sci. 2018, 75, 3521–3538. [Google Scholar] [CrossRef]
  31. Heneka, M.T.; Carson, M.J.; El Khoury, J.; Landreth, G.E.; Brosseron, F.; Feinstein, D.L.; Jacobs, A.H.; Wyss-Coray, T.; Vitorica, J.; Ransohoff, R.M.; et al. Neuroinflammation in Alzheimer’s Disease. Lancet Neurol. 2015, 14, 388–405. [Google Scholar] [CrossRef]
  32. Saraiva, C.; Praça, C.; Ferreira, R.; Santos, T.; Ferreira, L.; Bernardino, L. Nanoparticle-Mediated Brain Drug Delivery: Overcoming Blood-Brain Barrier to Treat Neurodegenerative Diseases. J. Control. Release 2016, 235, 34–47. [Google Scholar] [CrossRef]
  33. Silva, R.F.M.; Pogačnik, L. Food, Polyphenols and Neuroprotection. Neural Regen. Res. 2017, 12, 582–583. [Google Scholar] [CrossRef] [PubMed]
  34. Shahidi, F.; Ambigaipalan, P. Phenolics and Polyphenolics in Foods, Beverages and Spices: Antioxidant Activity and Health Effects—A Review. J. Funct. Foods 2015, 18, 820–897. [Google Scholar] [CrossRef]
  35. Raimondo, S.; Giavaresi, G.; Lorico, A.; Alessandro, R. Extracellular Vesicles as Biological Shuttles for Targeted Therapies. Int. J. Mol. Sci. 2019, 20, 1848. [Google Scholar] [CrossRef]
  36. Grabska-Kobyłecka, I.; Szpakowski, P.; Król, A.; Książek-Winiarek, D.; Kobyłecki, A.; Głąbiński, A.; Nowak, D. Polyphenols and Their Impact on the Prevention of Neurodegenerative Diseases and Development. Nutrients 2023, 15, 3454. [Google Scholar] [CrossRef]
  37. Liu, R.; Luo, C.; Pang, Z.; Zhang, J.; Ruan, S.; Wu, M.; Wang, L.; Sun, T.; Li, N.; Han, L.; et al. Advances of Nanoparticles as Drug Delivery Systems for Disease Diagnosis and Treatment. Chin. Chem. Lett. 2023, 34, 107518. [Google Scholar] [CrossRef]
  38. Asefy, Z.; Hoseinnejhad, S.; Ceferov, Z. Nanoparticles Approaches in Neurodegenerative Diseases Diagnosis and Treatment. Neurol. Sci. 2021, 42, 2653–2660. [Google Scholar] [CrossRef] [PubMed]
  39. Bao, Y.; He, J.; Song, K.; Guo, J.; Zhou, X.; Liu, S. Plant-Extract-Mediated Synthesis of Metal Nanoparticles. J. Chem. 2021, 2021, 6562687. [Google Scholar] [CrossRef]
  40. Bieschke, J.; Russ, J.; Friedrich, R.P.; Ehrnhoefer, D.E.; Wobst, H.; Neugebauer, K.; Wanker, E.E. EGCG Remodels Mature Alpha-Synuclein and Amyloid-Beta Fibrils and Reduces Cellular Toxicity. Proc. Natl. Acad. Sci. USA 2010, 107, 7710–7715. [Google Scholar] [CrossRef]
  41. Mu, J.; Zhuang, X.; Wang, Q.; Jiang, H.; Deng, Z.-B.; Wang, B.; Zhang, L.; Kakar, S.; Jun, Y.; Miller, D.; et al. Interspecies Communication between Plant and Mouse Gut Host Cells through Edible Plant Derived Exosome-like Nanoparticles. Mol. Nutr. Food Res. 2014, 58, 1561–1573. [Google Scholar] [CrossRef] [PubMed]
  42. Ehrnhoefer, D.E.; Bieschke, J.; Boeddrich, A.; Herbst, M.; Masino, L.; Lurz, R.; Engemann, S.; Pastore, A.; Wanker, E.E. EGCG Redirects Amyloidogenic Polypeptides into Unstructured, off-Pathway Oligomers. Nat. Struct. Mol. Biol. 2008, 15, 558–566. [Google Scholar] [CrossRef] [PubMed]
  43. Ono, K.; Tsuji, M.; Yamasaki, T.R.; Pasinetti, G.M. Anti-Aggregation Effects of Phenolic Compounds on α-Synuclein. Molecules 2020, 25, 2444. [Google Scholar] [CrossRef]
  44. Etheridge, M.L.; Campbell, S.A.; Erdman, A.G.; Haynes, C.L.; Wolf, S.M.; McCullough, J. The Big Picture on Nanomedicine: The State of Investigational and Approved Nanomedicine Products. Nanomed. Nanotechnol. Biol. Med. 2013, 9, 1–14. [Google Scholar] [CrossRef]
  45. Nyström, A.M.; Fadeel, B. Safety Assessment of Nanomaterials: Implications for Nanomedicine. J. Control. Release 2012, 161, 403–408. [Google Scholar] [CrossRef]
  46. Anand, B.G.; Dubey, K.; Shekhawat, D.S.; Kar, K. Capsaicin-Coated Silver Nanoparticles Inhibit Amyloid Fibril Formation of Serum Albumin. Biochemistry 2016, 55, 3345–3348. [Google Scholar] [CrossRef]
  47. Dehvari, M.; Ghahghaei, A. The Effect of Green Synthesis Silver Nanoparticles (AgNPs) from Pulicaria undulata on the Amyloid Formation in α-Lactalbumin and the Chaperon Action of α-Casein. Int. J. Biol. Macromol. 2018, 108, 1128–1139. [Google Scholar] [CrossRef]
  48. Wang, G.; Dai, J.; Lu, X. Scutellaria barbata Leaf Extract Mediated Gold Nanoparticles for Alzheimer’s Disease Treatment by Metal-Induced Amyloid β Aggregation Inhibition. J. Clust. Sci. 2020, 31, 1269–1273. [Google Scholar] [CrossRef]
  49. Qi, Y.; Yi, P.; He, T.; Song, X.; Liu, Y.; Li, Q.; Zheng, J.; Song, R.; Liu, C.; Zhang, Z.; et al. Quercetin-Loaded Selenium Nanoparticles Inhibit Amyloid-β Aggregation and Exhibit Antioxidant Activity. Colloids Surf. Physicochem. Eng. Asp. 2020, 602, 125058. [Google Scholar] [CrossRef]
  50. Zhao, N.; Yang, X.; Calvelli, H.R.; Cao, Y.; Francis, N.L.; Chmielowski, R.A.; Joseph, L.B.; Pang, Z.P.; Uhrich, K.E.; Baum, J.; et al. Antioxidant Nanoparticles for Concerted Inhibition of α-Synuclein Fibrillization, and Attenuation of Microglial Intracellular Aggregation and Activation. Front. Bioeng. Biotechnol. 2020, 8, 112. [Google Scholar] [CrossRef] [PubMed]
  51. Aliakbari, F.; Mohammad-Beigi, H.; Abbasi, S.; Rezaei-Ghaleh, N.; Lermyte, F.; Parsafar, S.; Becker, S.; Tafreshi, A.P.; O’Connor, P.B.; Collingwood, J.F.; et al. Multiple Protective Roles of Nanoliposome-Incorporated Baicalein against Alpha-Synuclein Aggregates. Adv. Funct. Mater. 2021, 31, 2007765. [Google Scholar] [CrossRef]
  52. Halder, T.; Patel, B.; Acharya, N. Design and Optimization of Myricetin Encapsulated Nanostructured Lipid Carriers: In-Vivo Assessment against Cognitive Impairment in Amyloid Beta (1-42) Intoxicated Rats. Life Sci. 2022, 297, 120479. [Google Scholar] [CrossRef]
  53. Andrade, S.; Loureiro, J.A.; Pereira, M.C. Transferrin-Functionalized Liposomes for the Delivery of Gallic Acid: A Therapeutic Approach for Alzheimer’s Disease. Pharmaceutics 2022, 14, 2163. [Google Scholar] [CrossRef]
  54. Ruan, Y.; Xiong, Y.; Fang, W.; Yu, Q.; Mai, Y.; Cao, Z.; Wang, K.; Lei, M.; Xu, J.; Liu, Y.; et al. Highly Sensitive Curcumin-Conjugated Nanotheranostic Platform for Detecting Amyloid-Beta Plaques by Magnetic Resonance Imaging and Reversing Cognitive Deficits of Alzheimer’s Disease via NLRP3-Inhibition. J. Nanobiotechnol. 2022, 20, 322. [Google Scholar] [CrossRef]
  55. Andrade, S.; Pereira, M.C.; Loureiro, J.A. Caffeic Acid Loaded into Engineered Lipid Nanoparticles for Alzheimer’s Disease Therapy. Colloids Surf. B Biointerfaces 2023, 225, 113270. [Google Scholar] [CrossRef]
  56. Zhang, M.; Li, Y.; Han, C.; Chu, S.; Yu, P.; Cheng, W. Biosynthesis of Nanoparticles with Green Tea for Inhibition of β-Amyloid Fibrillation Coupled with Ligands Analysis. Int. J. Nanomed. 2024, 19, 4299–4317. [Google Scholar] [CrossRef]
  57. Mirzaei-Behbahani, B.; Meratan, A.A.; Moosakhani, B.; Mohammad-Zaheri, M.; Mousavi-Jarrahi, Z.; Nikfarjam, N.; Shahsavani, M.B.; Saboury, A.A. Efficient Inhibition of Amyloid Fibrillation and Cytotoxicity of α-Synuclein and Human Insulin Using Biosynthesized Silver Nanoparticles Decorated by Green Tea Polyphenols. Sci. Rep. 2024, 14, 3907. [Google Scholar] [CrossRef]
  58. Mishra, G.; Awasthi, R.; Mishra, S.K.; Singh, A.K.; Tiwari, A.K.; Singh, S.K.; Nandi, M.K. Development of Epigallocatechin and Ascorbic Acid Dual Delivery Transferosomes for Managing Alzheimer’s Disease: In vitro and in vivo Studies. ACS Omega 2024, 9, 35463–35474. [Google Scholar] [CrossRef] [PubMed]
  59. Zhang, X.; Yao, W.; Zhou, H.; Wang, H.; Kong, B.; Bai, F. Ginkgo biloba Extract-Loaded PLGA Microcapsules Generated from Microfluidics for Alzheimer’s Disease Treatment. Mater. Des. 2024, 238, 112735. [Google Scholar] [CrossRef]
  60. Andrade, S.; Ramalho, M.J.; Loureiro, J.A.; Pereira, M.C. Mucoadhesive Chitosan-Modified PLGA Nanoparticles Loaded with Green Tea Extract Inhibit Amyloid β Peptide Aggregation and Oxidative Stress. J. Mol. Liq. 2025, 437, 128650. [Google Scholar] [CrossRef]
  61. Keramati, S.; Ahmadi, S.; Omidi, M.; Rezaeifar, F.; Shahsavani, M.B.; Meratan, A.A. Inhibition of Cytotoxic Fibrillation of Human Insulin Using Silver Nanoparticles Capped by Aqueous Extract of Echium amoenum. Sci. Rep. 2025, 15, 38756. [Google Scholar] [CrossRef]
  62. Gharb, M.; Mozafari, F.; Arghavani, P.; Saboury, A.A.; Riazi, G. Photochemically Synthesized Gold Nanoparticles Conjugated with Boswellic Acid Inhibit Alpha Synuclein Aggregation and Delay Fibrillation Kinetics. Sci. Rep. 2025, 15, 25886. [Google Scholar] [CrossRef] [PubMed]
  63. Hassan, S.H.; Sharaf, I.A.; Mohamed, A.S.; Salama, M.; Kamel, M.A.; Hafez, H.A. Green-Synthesized Silver Nanoparticles with Nigella sativa: A Multifaceted Approach against Parkinson’s Disease in Rats via MicroRNA Modulation. ACS Chem. Neurosci. 2025, 16, 3801–3815. [Google Scholar] [CrossRef]
  64. Barani, M.; Zargari, F.; Mirinejad, S.; Madani, F.; Hajinezhad, M.R.; Sargazi, S. Ginsenoside Rg3-Encapsulated Pegylated Niosomes Exhibit Multimodal Therapeutic Potential in Alzheimer’s Disease. Sci. Rep. 2025, 16, 2547. [Google Scholar] [CrossRef] [PubMed]
  65. Shirsat, S.D.; Li, C.; Liu, Z.; Achal, V.; Habimana, O. Anti-Amyloidogenic Properties of 5-caffeoylquinic Acid-Capped Selenium Nanoparticles. Sci. Rep. 2025, 15, 19460. [Google Scholar] [CrossRef] [PubMed]
  66. Isik, S.; Alhelwani, S.; Sahsahi, A.; Balcilar, H.; Yeman-Kiyak, B. Plant-Derived Exosome-like Nanovesicles: Mechanisms and Molecular Understanding in Neurological Disorders with Potential Therapeutic Applications. Drug Deliv. Transl. Res. 2025, 15, 4452–4478. [Google Scholar] [CrossRef]
  67. Reinke, A.A.; Gestwicki, J.E. Structure-Activity Relationships of Amyloid Beta-Aggregation Inhibitors Based on Curcumin: Influence of Linker Length and Flexibility. Chem. Biol. Drug Des. 2007, 70, 206–215. [Google Scholar] [CrossRef]
  68. Williams, R.J.; Spencer, J.P.E.; Rice-Evans, C. Flavonoids: Antioxidants or Signalling Molecules? Free Radic. Biol. Med. 2004, 36, 838–849. [Google Scholar] [CrossRef]
  69. Bejarano, E.; Cuervo, A.M. Chaperone-Mediated Autophagy. Proc. Am. Thorac. Soc. 2010, 7, 29–39. [Google Scholar] [CrossRef]
  70. Wilhelm, S.; Tavares, A.J.; Dai, Q.; Ohta, S.; Audet, J.; Dvorak, H.F.; Chan, W.C.W. Analysis of Nanoparticle Delivery to Tumours. Nat. Rev. Mater. 2016, 1, 16014. [Google Scholar] [CrossRef]
  71. Docter, D.; Strieth, S.; Westmeier, D.; Hayden, O.; Gao, M.; Knauer, S.K.; Stauber, R.H. No King without a Crown—Impact of the Nanomaterial-Protein Corona on Nanobiomedicine. Nanomedicine 2015, 10, 503–519. [Google Scholar] [CrossRef]
  72. Joyce, P.; Allen, C.J.; Alonso, M.J.; Ashford, M.; Bradbury, M.S.; Germain, M.; Kavallaris, M.; Langer, R.; Lammers, T.; Peracchia, M.T.; et al. A Translational Framework to DELIVER Nanomedicines to the Clinic. Nat. Nanotechnol. 2024, 19, 1597–1611. [Google Scholar] [CrossRef]
  73. Đorđević, S.; Gonzalez, M.M.; Conejos-Sánchez, I.; Carreira, B.; Pozzi, S.; Acúrcio, R.C.; Satchi-Fainaro, R.; Florindo, H.F.; Vicent, M.J. Current Hurdles to the Translation of Nanomedicines from Bench to the Clinic. Drug Deliv. Transl. Res. 2022, 12, 500–525. [Google Scholar] [CrossRef] [PubMed]
  74. Hajipour, M.J.; Safavi-Sohi, R.; Sharifi, S.; Mahmoud, N.; Ashkarran, A.A.; Voke, E.; Serpooshan, V.; Ramezankhani, M.; Milani, A.S.; Landry, M.P.; et al. An Overview of Nanoparticle Protein Corona Literature. Small 2023, 19, 2301838. [Google Scholar] [CrossRef]
  75. Önal Acet, B.; Gül, D.; Stauber, R.H.; Odabaşı, M.; Acet, Ö. A Review for Uncovering the “Protein-Nanoparticle Alliance”: Implications of the Protein Corona for Biomedical Applications. Nanomaterials 2024, 14, 823. [Google Scholar] [CrossRef]
  76. Sun, Y.; Zhou, Y.; Rehman, M.; Wang, Y.-F.; Guo, S. Protein Corona of Nanoparticles: Isolation and Analysis. Chem Bio Eng. 2024, 1, 757–772. [Google Scholar] [CrossRef]
  77. Uversky, V.N.; Oldfield, C.J.; Dunker, A.K. Intrinsically Disordered Proteins in Human Diseases: Introducing the D2 Concept. Annu. Rev. Biophys. 2008, 37, 215–246. [Google Scholar] [CrossRef]
  78. Fink, A.L. The Aggregation and Fibrillation of Alpha-Synuclein. Acc. Chem. Res. 2006, 39, 628–634. [Google Scholar] [CrossRef] [PubMed]
  79. Desai, N.; Rana, D.; Patel, M.; Bajwa, N.; Prasad, R.; Vora, L.K. Nanoparticle Therapeutics in Clinical Perspective: Classification, Marketed Products, and Regulatory Landscape. Small 2025, 21, 2502315. [Google Scholar] [CrossRef] [PubMed]
  80. Gawne, P.J.; Ferreira, M.; Papaluca, M.; Grimm, J.; Decuzzi, P. New Opportunities and Old Challenges in the Clinical Translation of Nanotheranostics. Nat. Rev. Mater. 2023, 8, 783–798. [Google Scholar] [CrossRef]
  81. Chou, W.-C.; Lin, Z. Impact of Protein Coronas on Nanoparticle Interactions with Tissues and Targeted Delivery. Curr. Opin. Biotechnol. 2024, 85, 103046. [Google Scholar] [CrossRef]
  82. Guo, F.; Luo, S.; Wang, L.; Wang, M.; Wu, F.; Wang, Y.; Jiao, Y.; Du, Y.; Yang, Q.; Yang, X.; et al. Protein Corona, Influence on Drug Delivery System and Its Improvement Strategy: A Review. Int. J. Biol. Macromol. 2024, 256, 128513. [Google Scholar] [CrossRef] [PubMed]
  83. Radeghieri, A.; Bergese, P. The Biomolecular Corona of Extracellular Nanoparticles Holds New Promises for Advancing Clinical Molecular Diagnostics. Expert Rev. Mol. Diagn. 2023, 23, 471–474. [Google Scholar] [CrossRef]
  84. Zhang, X.; Chan, H.W.; Shao, Z.; Wang, Q.; Chow, S.; Chow, S.F. Navigating Translational Research in Nanomedicine: A Strategic Guide to Formulation and Manufacturing. Int. J. Pharm. 2025, 671, 125202. [Google Scholar] [CrossRef] [PubMed]
  85. Rodríguez-Gómez, F.D.; Monferrer, D.; Penon, O.; Rivera-Gil, P. Regulatory Pathways and Guidelines for Nanotechnology-Enabled Health Products: A Comparative Review of EU and US Frameworks. Front. Med. 2025, 12, 1544393. [Google Scholar] [CrossRef]
  86. Reddy, P.H.; Tripathi, R.; Troung, Q.; Tirumala, K.; Reddy, T.P.; Anekonda, V.; Shirendeb, U.P.; Calkins, M.J.; Reddy, A.P.; Mao, P.; et al. Abnormal Mitochondrial Dynamics and Synaptic Degeneration as Early Events in Alzheimer’s Disease: Implications to Mitochondria-Targeted Antioxidant Therapeutics. Biochim. Biophys. Acta 2012, 1822, 639–649. [Google Scholar] [CrossRef] [PubMed]
  87. Faria, M.; Björnmalm, M.; Thurecht, K.J.; Kent, S.J.; Parton, R.G.; Kavallaris, M.; Johnston, A.P.R.; Gooding, J.J.; Corrie, S.R.; Boyd, B.J.; et al. Minimum Information Reporting in Bio-Nano Experimental Literature. Nat. Nanotechnol. 2018, 13, 777–785. [Google Scholar] [CrossRef]
  88. Welsh, J.A.; Goberdhan, D.C.I.; O’Driscoll, L.; Buzas, E.I.; Blenkiron, C.; Bussolati, B.; Cai, H.; Di Vizio, D.; Driedonks, T.A.P.; Erdbrügger, U.; et al. Minimal Information for Studies of Extracellular Vesicles (MISEV2023): From Basic to Advanced Approaches. J. Extracell. Vesicles 2024, 13, e12404. [Google Scholar] [CrossRef]
  89. Jo, H.Y.; Kang, S.J.; Kim, G.; Gwak, S.; Baek, G.; Rhee, W.J. Plant-Derived Extracellular Vesicles: Current Status and Challenges for Developing a New Paradigm in Therapeutics Development. VIEW 2025, 6, 20240115. [Google Scholar] [CrossRef]
  90. Sall, I.M.; Flaviu, T.A. Plant and Mammalian-Derived Extracellular Vesicles: A New Therapeutic Approach for the Future. Front. Bioeng. Biotechnol. 2023, 11, 1215650. [Google Scholar] [CrossRef]
  91. Meisl, G.; Knowles, T.P.J.; Klenerman, D. Mechanistic Models of Protein Aggregation Across Length-Scales and Time-Scales: From the Test Tube to Neurodegenerative Disease. Front. Neurosci. 2022, 16, 909861. [Google Scholar] [CrossRef] [PubMed]
Applsci 16 02620 g001
Figure 1. PRISMA-style flow diagram of study identification, screening, and inclusion.
Figure 1. PRISMA-style flow diagram of study identification, screening, and inclusion.
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Figure 2. Mechanistic pathways and translational challenges of plant-derived nanoparticles in modulating protein misfolding. (A) type of plant-derived nanoparticles; (B) mechanisms of action; (C) stpe towards clinical translation.
Figure 2. Mechanistic pathways and translational challenges of plant-derived nanoparticles in modulating protein misfolding. (A) type of plant-derived nanoparticles; (B) mechanisms of action; (C) stpe towards clinical translation.
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Table 1. Characteristics of experimental studies included in the qualitative synthesis of plant-derived nanomaterials targeting protein misfolding and aggregation (2015–2025).
Table 1. Characteristics of experimental studies included in the qualitative synthesis of plant-derived nanomaterials targeting protein misfolding and aggregation (2015–2025).
Author (Year)Nanomaterial TypePlant Source/PhytochemicalKey Characterization (Reported)Target Protein/ModelSystemAggregation EndpointsMain Outcome
Anand (2016) [46]Capsaicin-coated AgNPsCapsaicin (Capsicum)Size ~20–30 nm (reported in paper)BSA amyloid modelIn vitroDirect Strong suppression of BSA amyloid formation vs controls
Dehvari (2018) [47]Green AgNPsPulicaria undulata extractThT/TEM/CD, etc. reportedα-Lactalbumin amyloidIn vitroDirect (ThT, TEM, CD)Dose-dependent inhibition of fibril formation
Wang/Dai/Lu (2020) [48]Plant-extract AuNPsScutellaria barbata flavonoidsStandard AuNP characterization (reported)Metal-induced Aβ aggregationIn vitroDirectInhibition of metal-induced Aβ aggregation
Qi (2020) [49]Quercetin-loaded SeNPs QuercetinSize/ζ reportedAβ1–42 monomer aggregationIn vitro Direct + IndirectInhibits Aβ aggregation + antioxidant activity
Zhao (2020) [50]Antioxidant-delivery NPs (aggregation-inhibiting antioxidants)Antioxidant cargo (plant-derived class)NP specs reportedα-Syn aggregation + microglia activationIn vitro Direct + IndirectReduced α-Syn aggregation and pro-inflammatory activation
Aliakbari (2021) [51]Nanoliposome-incorporated baicaleinBaicalein (flavonoid)Size/ζ reportedα-Syn (PD-relevant)In vitro Direct + IndirectEnhanced protective effects vs free compound; aggregation/toxicity attenuation
Halder (2022) [52]Myricetin-NLCsMyricetinSize/encapsulation reportedAβ-induced AD rat modelIn vivoIndirect Improved brain bioavailability and cognition in Aβ model
Andrade (2022) [53]Tf-functionalized liposomes delivering polyphenolGallic acid (plant polyphenol)Size/ζ/stability reportedAβ aggregation contextIn vitroDirect Nano-delivery designed for anti-Aβ strategy
Ruan (2022) [54]Curcumin-conjugated nanotheranosticCurcuminMultifunctional nanomaterial characterizedAβ plaques (APP/PS1)In vivoIndirect Reduced Aβ plaque burden in APP/PS1 mice
Andrade (2023) [55]Tf-functionalized liposomes (CA-loaded)Caffeic acidStability + release; size reportedAβ aggregation/fibrilsIn vitroDirect Prevents Aβ aggregation and disaggregates mature fibrils
Zhang (2024) [56]Green tea biosynthesized AuNPs (GT-AuNPs)Green tea capping ligands (incl. EGCG, etc.)Size/ligands reportedAβ42 aggregation + disaggregationIn vitroDirectQuantified inhibition + promoted disaggregation
Mirzaei-Behbahani (2024) [57]Green tea polyphenol-capped AgNPsGreen tea polyphenolsSize/ζ, etc. reportedHuman insulin + α-syn fibrillationIn vitro Direct + IndirectStronger inhibition vs free polyphenols; reduced cytotoxicity/ROS
Mishra (2024) [58]Dual-drug nanoformulation (EGCG + AA)EGCG + ascorbic acidNP formulation characterizedAβ aggregation contextIn vitroDirect/Indirect Designed to enhance EGCG anti-aggregation potential via nanoformulation
Zhang (2024) [59]GBE-loaded PLGA microcapsulesGinkgo biloba extractMP/NP specs reportedAPP/PS1 miceIn vivoIndirect Reduced amyloid deposition; improved cognition
Andrade (2025) [60] Chitosan-modified PLGA NPsGreen tea extractNP specs reportedAβ aggregation + oxidative stressIn vitroDirect + IndirectInhibits Aβ aggregation and oxidative stress
Keramati (2025) [61]Plant-extract-capped AgNPsEchium amoenum extractNP specs + capping reportedHuman insulin fibrillationIn vitroDirect + IndirectInhibited cytotoxic fibrillation; improved cellular readouts
Gharb (2025) [62]Photochemically synthesized AuNP platformPlant-derived bioactive (BA) enhancedNanoplatform characterizedα-Syn aggregationIn vitroDirectInhibits α-Syn aggregation; translational framing
Hassan (2025) [63]Green AgNPsNigella sativaNP characterization reportedPD-like rats, α-SynIn vivoIndirectDecreased α-Syn aggregation, reduced inflammation/oxidative stress, improved behavior
Barani (2025) [64] PEGylated niosomesGinsenoside Rg3 (ginseng)Nanoformulation characterizedAD models (Aβ pathology)In vitro + in vivoIndirectReduced Aβ production/deposition markers; improved outcomes
Shirsat (2025) [65]Plant-polyphenol linked nano-system (AuNP-based)5-caffeoylquinic acidNano characterizedAβ-related assaysIn vitroDirect/Indirect Anti-amyloidogenic/disaggregation effects reported
Table 2. Qualitative assessment of methodological rigor across included experimental studies (2015–2025).
Table 2. Qualitative assessment of methodological rigor across included experimental studies (2015–2025).
Author (Year)Nanoparticle CharacterizationAggregation AssessmentBiological Model Relevance
Anand (2016) [46]AdequateDirectIn vitro
Dehvari (2018) [47]AdequateDirectIn vitro
Wang/Dai/Lu (2020) [48]AdequateDirectIn vitro
Qi (2020) [49]AdequateDirect + IndirectIn vitro
Zhao (2020) [50]PartialDirect + IndirectIn vitro
Aliakbari (2021) [51]AdequateDirect + IndirectIn vitro
Halder (2022) [52]AdequateIndirectIn vivo
Andrade (2022) [53]AdequateDirectIn vitro
Ruan (2022) [54]AdequateIndirectIn vivo
Andrade (2023) [55]AdequateDirectIn vitro
Zhang (2024) [56]AdequateDirectIn vitro
Mirzaei-Behbahani (2024) [57]AdequateDirect + IndirectIn vitro
Mishra (2024) [58]PartialDirect + IndirectIn vitro
Zhang (2024) [59]AdequateIndirectIn vivo
Andrade (2025) [60]AdequateDirect + IndirectIn vitro
Keramati (2025) [61]AdequateDirect + IndirectIn vitro
Gharb (2025) [62]AdequateDirectIn vitro
Hassan (2025) [63]AdequateIndirectIn vivo
Barani (2025) [64]AdequateIndirectIn vitro + In vivo
Shirsat (2025) [65]AdequateDirect + IndirectIn vitro
“Adequate” indicates that key physicochemical parameters (e.g., particle size distribution, zeta potential, and structural characterization) were reported. “Partial” indicates incomplete physicochemical reporting. Aggregation assessment refers to whether aggregation was directly quantified using biophysical assays or inferred from downstream biological endpoints.
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Toderescu, C.D.; Cresneac, I.; Oancea, A.; Trifunschi, S.; Munteanu, M.F.; Boru, C. Plant-Derived Nanomaterials and Protein Misfolding Disorders: Green Production Approaches, Biological Interactions, and Research Trends (2015–2025). Appl. Sci. 2026, 16, 2620. https://doi.org/10.3390/app16052620

AMA Style

Toderescu CD, Cresneac I, Oancea A, Trifunschi S, Munteanu MF, Boru C. Plant-Derived Nanomaterials and Protein Misfolding Disorders: Green Production Approaches, Biological Interactions, and Research Trends (2015–2025). Applied Sciences. 2026; 16(5):2620. https://doi.org/10.3390/app16052620

Chicago/Turabian Style

Toderescu, Corina Dalia, Iulia Cresneac, Alexandru Oancea, Svetlana Trifunschi, Melania Florina Munteanu, and Casiana Boru. 2026. "Plant-Derived Nanomaterials and Protein Misfolding Disorders: Green Production Approaches, Biological Interactions, and Research Trends (2015–2025)" Applied Sciences 16, no. 5: 2620. https://doi.org/10.3390/app16052620

APA Style

Toderescu, C. D., Cresneac, I., Oancea, A., Trifunschi, S., Munteanu, M. F., & Boru, C. (2026). Plant-Derived Nanomaterials and Protein Misfolding Disorders: Green Production Approaches, Biological Interactions, and Research Trends (2015–2025). Applied Sciences, 16(5), 2620. https://doi.org/10.3390/app16052620

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