Bioinspired Natural Product Nanoplatforms for Precision Cancer Theranostics from Nature to Nanomedicine

Abstract

Cancer is one of the leading health problems in the world because of tumor heterogeneity, resistance to therapy, and the fact that traditional interventions are relatively non-specific. Plant, marine, and microbial natural products exhibit varied anticancer properties, including regulation of apoptosis, oxidative stress, and multiple signaling pathways. Nevertheless, despite excellent mechanistic data, their clinical application remains constrained by poor solubility, low bioavailability, and instability, as well as by limited targeted delivery and biomarker-directed applications. In response to these issues, bioinspired nanoplatforms have emerged as a promising approach to improve the delivery and therapeutic efficacy of natural products. These systems involve biomimetic carrier systems, lipid-based and polymer-based nanoparticles, and stimuli-based nanomaterials, which can efficiently target the tumor, deliver the drugs in a controlled way, and improve pharmacokinetics. Moreover, they facilitate the combination of diagnostic imaging and therapy, which are the pillars of precision cancer theranostics. The present review introduces a comprehensive model that links natural product pharmacology, nanoplatform engineering, and interactions with the tumor microenvironment. It shows the importance of nano-bio interactions in drug uptake, distribution, and therapeutic response. Simultaneously, it critically addresses some of the most important translational challenges, including tumor heterogeneity, variability in delivery efficiency, lack of clinical validation, scaling issues, and regulatory complexity. Altogether, this review offers a balanced and integrated outlook, stating that biomarker-based approaches, standard design, and clinical relevance validation should be considered to develop natural product-based nanomedicine into an effective precision cancer theranostic strategy.

Graphical Abstract

Introduction

Despite advances in cancer research, the disease still poses a significant threat to health worldwide, and the complexity of tumor cell heterogeneity and therapeutic resistance, along with the limitations of traditional therapeutic approaches, is a challenge. Natural products derived from plant, marine and microbial origin show a variety of anticancer properties; however, these products are poorly soluble, unstable, have low bioavailability and lack of tumor specificity.¹ Among the new strategies developed to enhance the therapeutic effects, delivery and targeting of natural products, bioinspired nanoplatforms such as lipid based, polymeric, biomimetic, and stimuli-responsive systems have appeared as promising solutions. The advances would enable precision cancer theranostics, incorporating targeted therapy, personalized nanomedicine and monitoring of treatment in real time in one platform.² Nevertheless, the field of natural product pharmacology, nanotechnology, and precision oncology remains fragmented with many studies failing to address the important challenges of translation, including delivery variability, scalability, and clinical applications.³ This review thus combines natural products, bioinspired nanoplatforms, tumor microenvironment interactions and precision cancer theranostics to present a comprehensive overview and critically evaluates their potential and limitations in terms of translation. In order to overcome these challenges, we propose an integrated precision nanotheranostic framework (Figure 1) that consists of five interconnected layers: Natural product pharmacology, Nanocarrier engineering, Tumor microenvironment interactions, Imaging-guided therapy, and Clinical translation. This framework emphasizes the importance of coordination between the optimization of biological, engineering, and clinical aspects for creating effective precision cancer theranostics. The bibliometrics of the publications were analyzed using RStudio, VOSviewer, and OriginPro 2024 to evaluate publication trends, keyword frequency, and bibliographic coupling networks in this field (Figure 2A–C).

Figure 1.

An integrated precision nanotheranostic framework for natural product-based anticancer therapy. Natural product-derived anticancer agents are incorporated into advanced nanocarriers to improve bioavailability, targeted delivery, and stimuli-responsive release. Their efficacy is influenced by tumor microenvironment characteristics and cellular uptake, while theranostic platforms enable simultaneous therapy and imaging. Clinical translation requires scalable manufacturing, regulatory compliance, safety evaluation, and biocompatibility to enhance patient outcomes.

Figure 2.

Bibliometric analysis of “From Nature to Nanomedicine: Engineering Bioinspired Natural Product Nanoplatforms for Precision Cancer Theranostics”. (A) Year-wise distribution of publications showing the growth in research output from 2019 to 2026. (B) Keyword word cloud highlighting the most frequently occurring terms, including human, drug delivery system, targeted drug delivery, nanoparticles, nanomedicine, and review. (C) Bibliographic coupling network illustrating international collaboration and research linkages among leading countries in this field.

Methodology and Literature Search Strategy

The review was performed in a systematic way to ascertain the relevant literature pertinent to the natural products, bioinspired nanoplatforms, and precision cancer theranostics. The literature search was performed in electronic databases such as PubMed, Scopus, Web of Science and Google Scholar for articles published from 2000 to 2025. The following search strategy was used: natural products OR phytochemicals OR marine-derived compounds OR microbial metabolites AND nanomedicine OR nanoparticles OR bioinspired nanoplatforms AND cancer therapy OR oncology OR theranostics OR precision medicine. Articles on natural-product-based nanotherapeutics and cancer theranostics that are original research articles, reviews, clinical studies, or landmark publications were selected for inclusion. Articles not published in English, conference abstracts, editorials, patents, and studies which were not relevant to precision cancer applications were excluded. Titles and abstracts were then reviewed for relevance, and then the full text of eligible studies was assessed. Additional articles were identified through manual screening of reference lists. Recent publications, articles cited in the literature, clinically related investigations and reports detailing innovative advances in precision oncology and nanomedicine were prioritized.

Natural Products in Cancer Therapy

Classification and Sources (Plant, Marine, and Microbial)

Natural products are a wide range of anti-cancer drugs from plants, marine life and microorganisms. They are structurally diverse, biologically specific, and can be used to modulate multiple cellular pathways, making them ideal therapeutic agents in cancer therapy and precision nanomedicine. These compounds have played a major role in the development of clinically useful anticancer drugs and are still good candidates for new therapeutic agents.⁴

Plant-Derived Natural Products

Natural products from plants are still the most widely studied source of anticancer compounds. Major classes are alkaloids (vincristine and vinblastine), terpenoids (paclitaxel) and polyphenols (curcumin, quercetin, resveratrol, epigallocatechin gallate). They have been shown to have anticancer effects via several mechanisms such as induction of apoptosis, cell-cycle arrest, modulation of oxidative stress, inhibition of angiogenesis and regulation of signaling pathways including PI3K/Akt, NF-κB and MAPK pathways.^5,6 They have multi-targeted activity, which is very attractive against overcoming tumor heterogeneity and drug resistance. In plant-derived plants, however, bioactive substances often lack aqueous solubility, low bioavailability, chemical instability and environmental and extraction dependent variations that can affect the reproducibility of the therapeutic effect.⁷

Marine-Derived Natural Products

The marine ecosystem is a source of structurally unique bioactive compounds having high anticancer potential. The chemistry and stereochemistry of marine-derived agents are frequently unique and often complex, which is found less commonly in terrestrial organisms.⁸ Examples of clinically relevant drugs are trabectedin, isolated from the tunicate Ecteinascidia turbinata and which acts by binding to the DNA minor groove and interfering with transcription, and eribulin, a synthetic analogue of halichondrin B from marine sponges that affects the dynamics of microtubules.^9,10 Other marine-derived molecules such as bryostatin-1 (Bugula neritina), fucoidan (brown seaweeds), didemnin B (marine tunicates) and dolastatin analogues (marine cyanobacteria) have a variety of mechanisms such as protein kinase modulation, induction of apoptosis, immune regulation, and inhibition of microtubule assembly. These compounds have been used in liposomes, polymeric nanoparticles and biomimetic nanocarriers to increase stability, tumor targeting and pharmacokinetic properties, in order to enhance their therapeutic performance.¹¹ Although they have great promise, sustainable sourcing, low natural abundance, and complex synthesis are significant impediments to making them broadly clinically available.

Microbial-Derived Natural Products

Bacteria and fungi, especially, have given some of the most effective and successful anticarcinogenic medicines in clinical oncology. Well-known examples include the topoisomerase inhibitors and DNA intercalators such as doxorubicin, the nucleic acid synthesis inhibitors such as bleomycin and actinomycin D, and the DNA strand breakage suppressors mitomycin C, all of which have strong anti-cancer properties.¹² Recently, microbial metabolites like epothilones produced by Sorangium cellulosum and salinosporamide A from Salinispora tropica have garnered a lot of interest because of their activity against drug-resistant tumors and their defined targets. Due to their strong biological activity, compounds of microbial origin are used as extensively as possible in the development of nanoformulations such as liposomes, polymeric nanoparticles, nanostructured lipid carriers and targeted delivery systems, as they enable more optimized pharmacokinetics and lower systemic toxicity.¹³ Liposomal doxorubicin is one such case of successful clinical translation of nanomedicines. However, microbial metabolites can also have dose-limiting toxicities and variable therapeutic indices, which requires an advanced delivery strategy and the development of biomarker-guided applications.¹⁴

Collectively, plant-, marine-, and microbial-derived natural products provide complementary advantages for cancer therapy. Although plant-derived compounds have multi-targeted biological activities and are widely available, marine-derived metabolites have distinct chemical scaffolds (Figure 3) with high bioactivities and microbial products have provided several clinically approved anti-cancer drugs with defined modes of action. The combination of these varied natural products and the development of sophisticated nanoplatforms could broaden the scope of cancer precision theranostics and enable their clinical translation.

Figure 3.

Chemical structures of representative natural products and natural product-derived anticancer agents used in cancer theranostics and therapy. The figure illustrates the molecular structures of selected bioactive compounds, including flavonoids (apigenin, luteolin, quercetin, genistein), alkaloids (berberine, camptothecin), polyphenols (curcumin, resveratrol, epigallocatechin gallate), quinones (β-lapachone, thymoquinone), isothiocyanates (sulforaphane), polysaccharides (fucoidan), and clinically approved or investigational natural product-derived anticancer drugs such as doxorubicin, trabectedin, bryostatin-1, didemnin B, dolastatin analogues, eribulin, actinomycin D, bleomycin, epothilone B, mitomycin C, and salinosporamide A. These compounds exhibit diverse mechanisms of action and serve as important scaffolds for the development of nanotheranostic platforms and precision cancer therapeutics.

Molecular Mechanisms of Natural Products in Cancer Therapy

Natural products induce anticancer effects by causing apoptosis, reactive oxygen species (ROS) regulation, and oncogenic signaling pathway regulation, as shown in Figure 4. Although these mechanisms have been extensively reported, their translational applicability is limited, with the majority of evidence being obtained in preclinical models (Table 1). One of the major mechanisms is the induction of apoptosis. Mitochondrial pathways are activated by compounds such as apigenin, quercetin, and curcumin by altering Bcl-2 family proteins and caspases, frequently through the p53 signal transduction pathway. Paclitaxel causes mitotic arrest, and camptothecin causes topoisomerase inhibition, leading to DNA damage.^15,16 Nevertheless, a critical shortcoming is that most studies have shown apoptosis at very high concentrations, which are not feasible in vivo. Moreover, compensatory survival pathways often arise in tumor cells in response to resistance development, and these are not commonly considered in mechanistic studies.¹⁷

Figure 4.

Natural product-based precision cancer theranostics. Natural products from plant, marine, and microbial sources exert anticancer effects by regulating oxidative stress, mitochondrial function, apoptosis, and immune-related signaling pathways. In this figure, black arrows indicate the direction of mechanistic flow from source compounds to biological effects and from limitations to proposed solutions, red starburst symbols represent reactive oxygen species (ROS), green arrows indicate modulation of ROS-related signaling by natural products, and the red cross denotes the main barriers to clinical translation. These barriers include poor solubility, low bioavailability, rapid metabolism, lack of clinical validation, toxicity, and non-specific targeting. Nanocarrier-based delivery systems are shown as the proposed solution because they improve stability, targeted delivery, biomarker-driven therapy, and overall therapeutic efficacy, supporting precision oncology.

Table 1.

Molecular Mechanisms of Representative Natural Products in Cancer Therapy with Experimental Evidence and Translational Limitations

Natural Product	Source	Key Mechanism	Molecular Targets	Model System	Key Outcome	Translational Limitation	Reference
Plant-Derived Natural Products
Apigenin	Plant (parsley, chamomile)	Cell cycle arrest, apoptosis	p53, PI3K/Akt	In vitro, in vivo	Anti-tumor activity	Poor solubility	[18]
Berberine	Plant (Berberis spp).	Apoptosis, metabolic stress	AMPK, mitochondrial pathways	In vitro, in vivo	Tumor growth inhibition	Poor absorption	[19]
β-lapachone	Plant-derived quinone	ROS-mediated cell death	NQO1-dependent redox cycling	Preclinical	Selective tumor cytotoxicity	Biomarker dependency, toxicity risk	[20]
Camptothecin	Plant (Camptotheca)	DNA damage	Topoisomerase I inhibition	Preclinical/clinical derivatives	Anti-tumor activity	Instability, toxicity	[21]
Curcumin	Plant (Curcuma longa)	Apoptosis, ROS modulation	NF-κB, PI3K/Akt, Bcl-2	In vitro, in vivo	Anti-proliferative, pro-apoptotic	Poor bioavailability, rapid metabolism	[22]
Doxorubicin	Microbial (Streptomyces)	ROS generation, DNA damage	Topoisomerase II inhibition	Clinical	Broad anticancer activity	Cardiotoxicity, off-target effects	[23]
Epigallocatechin gallate (EGCG)	Plant (green tea)	Anti-oxidant/pro-oxidant switch, apoptosis	MAPK, NF-κB	In vitro, in vivo	Reduced tumor growth	Instability, low plasma levels	[24]
Genistein	Plant (soy)	Cell cycle arrest, apoptosis	Tyrosine kinases, PI3K/Akt	In vitro, animal	Anti-proliferative	Hormone-like effects, variability	[25]
Luteolin	Plant (herbs)	Apoptosis, anti-inflammatory	NF-κB, STAT3	In vitro	Reduced proliferation	Limited in vivo validation	[26]
Paclitaxel	Plant (Taxus spp).	Mitotic arrest	Microtubule stabilization	Clinical	Tumor regression	Drug resistance, systemic toxicity	[27]
Quercetin	Plant (fruits, vegetables)	ROS induction, apoptosis	PI3K/Akt, caspases	In vitro, in vivo	Growth inhibition	Poor solubility, low bioavailability	[28]
Resveratrol	Plant (grapes, berries)	Apoptosis, anti-proliferative	p53, NF-κB, MAPK	In vitro, animal	Cell cycle arrest, apoptosis	Low stability, rapid clearance	[29]
Sulforaphane	Plant (cruciferous vegetables)	ROS modulation, detoxification	Nrf2 activation, HDAC inhibition	In vitro, early clinical	Chemopreventive effects	Dose variability, instability	[30]
Thymoquinone	Plant (Nigella sativa)	ROS generation, apoptosis	NF-κB, p53	In vitro, in vivo	Anti-cancer effects	Poor pharmacokinetics	[31]
Trabectedin	Marine (Ecteinascidia)	DNA binding, transcription inhibition	DNA minor groove binding	Clinical	Effective in sarcoma, ovarian cancer	Complex synthesis, toxicity	[32]
Marine-Derived Natural Products
Bryostatin-1	Bugula neritina	Protein kinase modulation	PKC signaling	In vitro, clinical Trials	Anti-proliferative activity	Limited availability	[33]
Didemnin B	Marine tunicates	Protein synthesis inhibition	EF-1α	Clinical Trials	Induction of apoptosis	Toxicity concerns	[34]
Dolastatin analogues	Marine cyanobacteria	Microtubule disruption	Tubulin	Clinical/ADC development	Potent cytotoxic activity	Limited natural supply	[11]
Eribulin	Marine sponge derivative (Halichondrin B analogue)	Microtubule inhibition	Tubulin dynamics	Clinical	Improved overall survival in metastatic cancers	Peripheral neuropathy	[35, 36]
Fucoidan	Brown seaweeds	Apoptosis, immune modulation	PI3K/Akt, MAPK	In vitro, In vivo	Reduced tumor growth and angiogenesis	Structural variability	[37]
Trabectedin	Ecteinascidia turbinata	DNA binding, transcription inhibition	DNA minor groove	Clinical	Effective in sarcoma and ovarian cancer	Complex synthesis	[38]
Microbial-Derived Natural Products
Actinomycin D	Streptomyces parvulus	Transcription inhibition	DNA-dependent RNA synthesis	Clinical	Inhibition of tumor proliferation	Systemic toxicity	[39]
Bleomycin	Streptomyces verticillatus	DNA strand breaks	DNA damage pathways	Clinical	Effective tumor regression	Pulmonary toxicity	[10]
Doxorubicin	Streptomyces peucetius	DNA damage, ROS generation	Topoisomerase II	Clinical	Broad-spectrum anticancer activity	Cardiotoxicity	[40]
Epothilone B	Sorangium cellulosum	Microtubule stabilization	β-Tubulin	Clinical/Approved derivative	Activity against taxane-resistant tumors	Neurotoxicity	[41]
Mitomycin C	Streptomyces caespitosus	DNA crosslinking	DNA replication pathways	Clinical	Cytotoxic activity against solid tumors	Myelosuppression	[42]
Salinosporamide A	Salinispora tropica	Proteasome inhibition	20S Proteasome	Clinical trials	Potent activity against resistant tumors	Limited clinical validation	[43]

ROS modulation is a context-dependent mechanism, where β-lapachone and thymoquinone augment ROS to promote oxidative stress-mediated cell death, and doxorubicin is a combination of both ROS generation and DNA damage.²⁰ On the contrary, EGCG and resveratrol have dual antioxidant and pro-oxidant effects that vary with dose and cell conditions. Such a duality introduces variability and can lead to unreliable therapeutic outcomes. Notably, overinduction of ROS can also cause harm to normal tissues, which is also a safety concern that is frequently not reported in preclinical trials.⁴⁴

Other signaling pathways regulated by natural products include PI3K/Akt, NF-κB, and MAPK. Curcumin, genistein and quercetin prevent survival signaling, whereas sulforaphane regulates epigenetic homeostasis by HDAC inhibition and Nrf2 activation. Multi-target modulation is also beneficial because it helps to deal with tumor heterogeneity, but it represents a relatively non-specific mechanism of action.⁴⁵ Such non-selectivity increases the likelihood of off-target effects and makes dose optimization difficult, especially in clinical practice. Certain compounds are also mechanism-linked and specific, eg, 8-hydroxy-naphtho-1,2-benzo-dicarboxylic acid requires NQO1 to be expressed, and trabectedin, which requires transcriptional regulation. These are indications of biomarker-directed therapy. Nevertheless, the majority of phytoconstituents do not have this stratification framework and are restricted in their application for precision oncology.¹ One of the most significant overall limitations is the lack of connection between mechanistic claims and clinical validation. Numerous investigations are conducted on single-pathway modulation of simplified in vitro models, but tumors are governed by complicated, adaptive networks. In addition, therapeutic drug concentrations are not achieved in patients due to pharmacokinetic limitations. Consequently, the multi-pathway reported activity can be an overestimation of clinical efficacy.⁴⁶

Overall, natural products exhibit a wide range of mechanistic actions during apoptosis, oxidative stress, and signaling pathways. Nonetheless, they have limited specificity, are context-dependent, lack in vivo validation, and are not biomarker-driven, limiting their translation to the clinic. These gaps need a rational formulation and stratification of a patient to pursue natural products towards precision cancer therapy.⁴⁷

Limitations of Natural Products in Cancer Therapy

The clinical translation of natural products remains constrained by key pharmacodynamics and pharmacokinetics, despite strong mechanistic evidence. This is a significant obstacle due to poor solubility. Compounds such as curcumin, quercetin, and apigenin have poor water solubility, leading to limited systemic exposure. This has led to a high number of reported in vitro effects that cannot be reproduced in vivo, thereby overestimating therapeutic potential. Unpredictability and increased metabolism also decrease effectiveness. Curcumin and EGCG, for example, degrade rapidly, which limits their half-life and bioactivity.³ Significantly, active metabolites are not analyzed in the majority of studies to determine whether they are involved in or reduce therapeutic effects. A major limitation is low bioavailability. Phytoconstituents like resveratrol and berberine have low absorption and clearance and cannot be accumulated in the tumor. This is partially the reason why a number of compounds with high mechanistic profiles have failed to translate into clinical success.⁴⁸ There is also a problem of off-target effects and toxicity. Natural product-based drugs like doxorubicin and paclitaxel are said to be safe, however, they have been associated with serious side effects. Further, due to the multi-target nature of phytochemicals, there are higher chances that they may have non-specific interactions, which are never evaluated for efficacy. One such weakness is the absence of PK-PD correlation and clinical validation.⁴⁹ There are numerous publications that show pathway modulation (eg, NF-/Akt PI3K) without an effective in vivo concentration. Moreover, the majority of compounds do not have biomarker-directed applications, and this restricts their use in precision oncology. In general, the shift of mechanistic promise to clinical application is limited by low bioavailability, poor solubility, instability, as well as low specificity. These restrictions highlight the importance of the development of sophisticated delivery systems and realistic design approaches to facilitate successful translation.⁵⁰

Analytical Standardization and Quality Control of Natural Products Prior to Nanoencapsulation

The clinical translation of the nanomedicines based on natural products needs intensive analytical standardization of the natural raw extracts before nanoencapsulation (Table 2). Natural products are always a mixture, although their phytochemical composition can change depending on where they are grown, how they are grown, when they are picked, how they are extracted and how they are stored. This variability may have a significant effect on biological activity, loading efficiency of nanoparticles, release kinetics and therapeutic effects.⁵¹

Table 2.

Analytical Standardization and Quality Control of Natural Product Extracts

Method	Purpose	Key Output	GMP/QC Relevance	References
Metabolomics	Global phytochemical profiling	Chemical fingerprint	Batch consistency	[52]
LC-MS/MS	Marker and impurity analysis	Quantitative profile	Release testing	[13]
NMR Profiling	Structural characterization	Authentication	Detects adulteration	[53]
HPLC/UHPLC	Active compound quantification	Purity and content	Routine QC	[54]
Stability Studies	Shelf-life assessment	Degradation profile	Stability validation	[55]
Impurity Testing	Contaminant detection	Safety profile	Regulatory compliance	[56]
Chemometrics	Batch classification	Quality prediction	Process control	[57,58]
Quality-by-Design	Process optimization	Critical quality attributes	GMP implementation	[59]

Advanced metabolomic guided standardization has proved to be a powerful approach for the comprehensive characterization of phytochemical profiles. Profiling of bioactive compounds, detection of batch-to-batch variations, and the creation of chemical fingerprints linked to therapeutic efficacy are possible with both untargeted and targeted metabolomic approaches.⁶⁰ Another major advantage of liquid chromatography–tandem mass spectrometry (LC-MS/MS) fingerprinting is the quantitative evaluation of marker compounds, impurity profiling and degradation products, and quality consistency across production batches.⁶¹

Moreover, NMR-based phytochemical profiling offers a powerful and non-destructive structure characterization and authentication tool and method for adulterant detection.⁶² NMR metabolomics can be used in a complementary way to LC-MS/MS, as it allows one to assess the overall composition of extracts and the long-term chemical stability of the extracts. These two methods complement each other in formulating a standardized phytochemical reference profile which is crucial for a reproducible nanoformulation development.^60,63

Regulatory-wise, Good Manufacturing Practice (GMP) compliant production calls for the following acceptance criteria: phytochemical content, levels of impurities, residual solvents, microbial contamination, and stability parameters. The application of metabolomics, chromatographic fingerprinting and spectroscopic profiling to quality-by-design (QbD) can help to ensure reproducibility, facilitate process validation and increase the reagulatory acceptance of nanomedicines from natural sources.⁶⁴ Therefore, advanced analytical standardization is deemed to be a key prerequisite for the development of precision nanotheranostics and translation to the clinical field.

Engineering Bioinspired Natural Product Nanoplatforms

Poor solubility, instability and low bioavailability are disadvantages of natural products that have also led to the creation of engineered nanoplatforms, as shown in Figure 5. Nanotechnology involves bioinspiration so as to enhance delivery efficiency, tumor specificity and controlled release. Nevertheless, these systems have potential, but their clinical implementation is limited by the complexity of the designs, scalability challenges, and the lack of human model validation.

Figure 5.

Advanced nanoplatforms for natural product-based precision cancer therapy. Nano-formulation systems, biomimetic nanocarriers, surface-functionalized nanoparticles, and stimuli-responsive nanoplatforms enhance the bioavailability, tumor targeting, immune evasion, and controlled release of natural products, thereby improving therapeutic efficacy while addressing challenges related to scalability, reproducibility, tumor heterogeneity, and clinical translation. Black arrows indicate the direction of nanocarrier transport, targeting, and release pathways. Curved arrows represent active targeting and intracellular internalization. Upward arrows (↑) indicate increased levels or activity, including GSH↑ (increased glutathione) and MMP↑ (increased matrix metalloproteinase activity). Downward arrows (↓) indicate decreased levels, including O₂↓ (hypoxia/reduced oxygen). The pH color gradient represents the acidic tumor microenvironment. CD47 denotes immune evasion, while the terms RBC, HER2, folate R, and transferrin R refer to red blood cells, HER2 receptor, folate receptor, and transferrin receptor, respectively.

Biomimetic Nanocarriers

Biomimetic nanocarriers are engineered to offer improved performance for the delivery of natural products through their ability to mimic biological structures, which extends circulation time, immune clearance and target tumors. Coated nanoparticles in the blood with red blood cell membranes make use of CD47-mediated self-recognition to achieve long circulation time, whereas cancer cell membrane-coated systems allow homologous tumor targeting.⁶⁵ Natural chemotactic pathways are activated by functionalizing immune cell membranes with nanoparticles to promote the infiltration of tumors, and exosome-like carriers are used for cellular uptake and biocompatibility of sensitive phytochemicals. These platforms provide a link between biological activity of natural products and sophisticated delivery systems⁶⁶ (Table 3).

Table 3.

Bioinspired Nanoplatforms for Natural Product Delivery: Design Strategies, Advantages, and Translational Considerations

Nanoplatform Type	Design Strategy	Natural Products Used	Key Advantage	Translational Limitation	Reference
RBC membrane-coated NPs	Biomimetic immune evasion	Paclitaxel, Curcumin	Prolonged circulation	Lack of active targeting	[67]
Cancer cell membrane-coated NPs	Homologous targeting	Doxorubicin, Resveratrol	Tumor-specific recognition	Tumor heterogeneity, safety	[68]
Immune cell membrane-coated NPs	Inflammation-guided delivery	Quercetin, Luteolin	Improved tumor penetration	Variable biodistribution	[69]
Exosome-inspired systems	Natural vesicle-based delivery	Genistein, Sulforaphane	High biocompatibility	Scalability, standardization	[70]
Liposomes	Lipid bilayer encapsulation	Berberine, Thymoquinone	Improved solubility	Leakage, stability issues	[71]
Polymeric nanoparticles	Biodegradable polymers	Apigenin, Honokiol	Controlled release	Complex synthesis	[72]
Nanoemulsions	Oil–water dispersion	EGCG, Gambogic acid	Enhanced absorption	Physical instability	[73]
Solid lipid nanoparticles (SLNs)	Solid lipid matrix	Kaempferol, Baicalein	Improved stability	Limited drug loading	[74]
Nanostructured lipid carriers (NLCs)	Mixed lipid systems	Naringenin, Silibinin	Higher drug loading	Formulation complexity	[75]
Dendrimers	Branched polymer structures	Camptothecin, Betulinic acid	High drug loading	Toxicity, cost	[76]
Metallic nanoparticles (Au, Ag)	Inorganic core systems	Epigallocatechin gallate (EGCG), Fisetin	Imaging + photothermal capability	Long-term toxicity	[77]
Mesoporous silica nanoparticles	Porous inorganic carriers	Luteolin, Emodin	High loading capacity	Biodegradability concerns	[78]
Carbon-based nanomaterials	Graphene, CNTs	Sulforaphane, Chrysin	High surface area	Toxicity, poor clearance	[79]
Targeted nanoparticles	Ligand-functionalized systems	Honokiol, Allicin	Enhanced uptake	Protein corona masking	[80]
Stimuli-responsive nanoparticles	pH/redox/enzyme-triggered	β-lapachone, Plumbagin	Controlled release	Tumor variability	[81]
Magnetic nanoparticles	External field-guided delivery	Artesunate, Andrographolide	Controlled localization	Limited clinical validation	[82]
Hybrid nanoplatforms	Organic–inorganic systems	Gambogic acid, Oridonin	Multifunctionality	Complex fabrication	[83]

Although these benefits exist, clinical translation is difficult because of immunogenicity, donor-to-donor variability, potential for contamination, potential for lack of reproducibility, and manufacturing difficulties. The source, preparation, and storage of membranes can vary greatly and thus significantly influence the properties of nanoparticles, their biodistribution, and the therapeutic results.⁸⁴ Furthermore, targeted improvements are not necessarily followed by drug efficacy because the release kinetics of the drug and its bioavailability in the intracellular environment are still factors that determine the efficacy of treatment. Strategies to overcome these challenges will involve strict standardization, quality control, scalable manufacturing and validation in clinically relevant tumor models.⁸⁵

Nanoformulation Strategies (Liposomes, Polymeric Nanoparticles, Nanoemulsions)

Nanoformulation approaches provide the basis for translating natural products into clinically applicable nanomedicines and for achieving affordability in precision cancer theranostics.⁸⁶ Poor solubility, instability, and low bioavailability are limitations that can be overcome using liposomes, polymeric nanoparticles, and nanoemulsions. Liposomes are made of phospholipid bilayers and can contain both hydrophilic and hydrophobic substances, protecting them and prolonging circulation.⁸⁷ Compounds such as resveratrol and berberine have been used with this strategy to enhance stability and systemic exposure. Apigenin and honokiol are natural products whose release can be controlled and sustained using polymeric nanoparticles made of biodegradable polymers, which allow for retention of therapeutic levels over time. Nanoemulsions enhance the solubility and absorption of hydrophobic molecules like EGCG and gambogic acid, and so they increase their pharmacokinetic characteristics. Moreover, imaging agents can be integrated into these platforms, enabling both diagnostic and therapeutic capabilities, which are core to theranostics⁸⁸ (Table 3).

But the clinical implementation of such systems is constrained by several factors. Nanoformulations that exploit the enhanced permeability and retention (EPR) effect to accumulate in tumors have been used in many studies, yet their effectiveness is highly tumor- and patient-specific, not always applicable to human tumors, and significantly less effective in human tumors than in preclinical models.⁸⁹ Moreover, the treatment efficacy can be diminished by such issues as low drug loading efficacy, premature leakage of drugs, and their instability in storage. Although better pharmacokinetics are most often observed, such improvements are not necessarily translated into meaningful clinical outcomes, such as improved survival or decreased toxicity.⁹⁰ According to Table 3, nanoformulation approaches can be used to overcome the physicochemical drawbacks of natural products, but their applicability in precision cancer theranostics needs to be enhanced by improving reproducibility, controlling drug release, and using clinically relevant models.

Surface Functionalization and Active Targeting

An important strategy for increasing the specificity of nanoplatforms and active targeting of tumor cells is surface functionalization. Nanoparticles can effectively target receptors overexpressed on cancer cells, including folate receptors, transferrin receptors, and HER2, by binding to these receptors via attached ligands such as antibodies, peptides, or small molecules. This specific contact enhances the uptake and cellular and intracellular delivery of natural products, especially those with low membrane permeability, such as honokiol and sulforaphane.⁹¹ Moreover, nanoplatforms with surface functionalization can be used with imaging agents to visualize the distribution of nanoparticles in real time and enable precision theranostic applications (Table 3).

Active targeting increases delivery efficiency, improving cellular internalization and minimizing off-target effects, thereby increasing the therapeutic index of the delivery. Its effectiveness, however, depends on the expression of target receptors, which may differ between patients and between different parts of a tumor. Moreover, they can form a protein corona when interacting with biological fluids, thereby concealing targeting ligands and reducing binding efficiency.⁹² As discussed in Table 3, surface functionalization is expected to enhance both specificity and uptake, but its clinical effectiveness requires overcoming biological variation and showing a consistent therapeutic effect. Therefore, this approach is a valuable step toward custom nanomedicine, as it combines diagnostic molecular tumor features with delivery to targeted systems.

Stimuli-Responsive and Smart Delivery Systems

Stimuli-responsive nanoplatforms are expected to deliver natural products to tumor-associated conditions, including acidic pH, redox gradient, enzyme activity, and hypoxia. These systems enable site-controlled and regulated drug release, enhance therapeutic effectiveness, and reduce systemic toxicity. As an example, redox-responsive nanoparticles increase the delivery of 2-lapachone by exploiting high glutathione levels in the cell, and pH-sensitive systems release plumbagin in acidic tumor cells.⁹³ These types of designs are especially beneficial for natural products and safeguard the drug during circulation, releasing it at the target site, thereby enhancing treatment precision (Table 3).

These systems are also used in theranostic applications (combining diagnostic and therapeutic capabilities on a single platform) and for controlled release. To enhance reliability in heterogeneous tumor settings, where a single stimulus may not be effective, multi-responsive nanoplatforms have the potential to enhance reliability. Spatial and temporal control of drug release can also be improved by external stimuli, such as light, temperature or magnetic fields.⁹⁴ Nevertheless, system complexity can negatively impact reproducibility, scalability, and regulatory approval. The most important difficulty, as described in Table 3, is striking the right balance between functional sophistication and practical feasibility. Consequently, stimuli-responsive nanoplatforms represent an important breakthrough in the gap between natural products and precision cancer theranostics, enabling adaptive, controlled, and patient-specific treatment approaches.⁹¹

To enhance the translational aspect, nanoplatforms are categorized into clinical, early clinical, preclinical, and experimental based on the level of evidence (Table 4). The classification emphasizes that traditional liposomes have made it to the clinical stage, while most biomimetic, stimuli-responsive, and multifunctional systems are still in preclinical stages. The gap highlights the necessity to develop better standardization, to design nanomedicines using biomarkers and to validate these products clinically quickly to enable translation of natural product-based nanomedicines.⁹⁵

Table 4.

Comparative Assessment and Translational Status of Nanoplatforms for Natural Product-Based Precision Cancer Theranostics

Technology	Representative Systems	Evidence Level	Clinical Status	Loading Efficiency (%)	Half-Life (h)	Targeting	Key Limitation	Key Reference
Liposomes	Curcumin, Resveratrol liposomes	Clinical	Approved	60–95	8–48	Moderate	Drug leakage	[96]
Polymeric NPs	Apigenin, Honokiol NPs	Preclinical–Early Clinical	Emerging	50–90	12–72	Moderate	Scale-up complexity	[97]
Nanoemulsions	EGCG, Gambogic acid systems	Preclinical	Emerging	40–80	2–24	Low–Moderate	Physical instability	[98]
SLNs/NLCs	Kaempferol, Naringenin systems	Preclinical	Emerging	60–90	8–48	Moderate	Formulation complexity	[99]
Biomimetic Nanocarriers	RBC/Cancer-cell membrane NPs	Preclinical	Experimental	50–85	24–120	High	Reproducibility	[100]
Exosome-Inspired Systems	Genistein, Sulforaphane systems	Preclinical	Experimental	40–80	24–96	High	Standardization	[101,102]
Targeted NPs	Ligand-functionalized systems	Preclinical	Emerging	50–90	12–72	High	Protein corona	[103]
Stimuli-Responsive NPs	pH/Redox-responsive systems	Preclinical	Experimental	40–85	12–72	High	Tumor heterogeneity	[104]
Hybrid/Multifunctional Systems	Chemo + PDT/PTT platforms	Experimental–Preclinical	Emerging	50–95	12–96	Very High	Regulatory complexity	[105]

To summarize, the therapeutic and translational efficacy of the major nanoplatforms reviewed here are summarized in Table 4, which compares their drug loading efficiency, circulation half-life, targeting ability, clinical maturity and key limitations.

Conventional platforms, like liposomes, have attained high drug loading efficiency (60–95%) and are the most clinically accepted platforms because they have well-established production processes and regulatory approvals (Table 4). Polymeric nanoparticles, SLNs/NLCs and targeted nanoparticles offer better drug retention and controlled release and are still in the process of being clinically translated. Biomimetic, exosome-inspired, stimuli-responsive, and multifunctional nanoplatforms exhibit extended circulation time, targeting effect, and therapeutic multiprocess capabilities; however, there remains significant hurdles that need to be addressed in the context of reproducibility, scalability, manufacturing complexity, cost, and regulatory acceptance. The comparisons clearly indicate that while the advanced functionalities are highly desirable, they are not translation-ready, which clearly highlights the need for standardized and clinically scalable nanoplatform designs for precision cancer theranostics.

Nano–Bio Interactions in the Tumor Microenvironment

Bioinspired nanoplatforms have a substantial impact on their interactions with the tumor microenvironment (TME) that defines their therapeutic performance. This is a highly dynamic environment and comprises cancer cells, stromal elements, immune cells, abnormal vasculature, and biochemical gradients. All of these affect the uptake, distribution, and drug release of nanoparticles. It is important to understand nano-bio interactions to translate natural product-based nanomedicines into effective precision cancer theranostics.¹⁰⁶ The major mechanisms of interaction and translational implications are listed in Table 5.

Table 5.

Nano–Bio Interactions in the Tumor Microenvironment: Mechanisms, Impact on Delivery, and Translational Considerations

Interaction Aspect	Mechanism	Impact on Natural Product Delivery	Example Strategy	Translational Challenge	Reference
Cellular uptake	Endocytosis (clathrin, caveolae, macropinocytosis)	Determines intracellular drug availability	Ligand-functionalized nanoparticles	Variable uptake across cell types	[107]
Intracellular trafficking	Endosomal–lysosomal pathway	Drug degradation or controlled release	pH-sensitive carriers	Inefficient endosomal escape	[108]
Endosomal escape	Proton sponge effect, membrane disruption	Enables cytosolic drug delivery	Polymeric/peptide systems	Limited efficiency, toxicity	[109]
Tumor pH responsiveness	Acidic microenvironment	Site-specific drug release	pH-responsive nanocarriers	pH heterogeneity	[110]
Enzyme-responsive delivery	Proteases (MMPs, cathepsins)	Triggered drug activation	Enzyme-cleavable linkers	Enzyme variability	[111]
Hypoxia-responsive systems	Low oxygen levels	Targets resistant tumor regions	Hypoxia-activated systems	Inconsistent hypoxia	[112]
Redox-responsive delivery	Elevated glutathione (GSH)	Intracellular drug release	Disulfide bond systems	Redox variability	[113]
Tumor penetration	Dense extracellular matrix (ECM)	Limits deep drug diffusion	ECM-modulating nanoparticles	Poor penetration in solid tumors	[114]
Interstitial fluid pressure (IFP)	Elevated tumor pressure	Reduces nanoparticle transport	Pressure-modulating strategies	Limited clinical control	[115]
Vascular permeability	Leaky vasculature (EPR effect)	Enables passive targeting	Liposomes, polymeric NPs	Variable in humans	[116]
Protein corona formation	Patient-specific adsorption of plasma proteins onto nanoparticles	Alters biodistribution, targeting, and immune interactions	Personalized proteomic profiling	Inter-patient variability and prediction of clinical performance	[117]

Cellular Uptake and Intracellular Trafficking

One critical process that defines the intracellular accessibility of natural products released by nanoplatforms is cellular uptake. The endocytic systems into which nanoparticles are absorbed include clathrin-mediated, caveolae-mediated and macropinocytosis. The physicochemical properties, such as size, surface charge, and functionalization, affect uptake efficiency. Nanoparticles with dimensions between 50 and 150nm tend to be more highly taken up in tumor cells, and surface modification with targeting ligands can augment internalization between 25 and 5-fold in preclinical models.¹¹⁸ Nonetheless, positively charged systems that are effective in uptake might enhance non-specific interactions and toxicity. Cell uptake is not homogeneous and varies with tumor type and cellular conditions, as shown in Table 5. After internalization, nanoparticles are transported to the endosomal-lysosomal pathway, where the acidic conditions allow enzymes to degrade the drug.¹¹⁹ To circumvent this, the proton sponge effect and pH-sensitive materials are employed to enhance endosomal escape, thereby greatly improving cytosolic drug delivery. These methods, however, can be toxic and less efficient across all cell types. Moreover, the heterogeneity of tumor cells and the protein composition of the tumor microenvironment may also alter uptake modes and reduce targeting efficacy. Intracellular variability is a significant obstacle, and it implies that uptake and endosomal escape should be optimized to enhance the successful delivery of nanomedicine-based natural product delivery.¹²⁰

Tumor Microenvironment-Responsive Delivery (pH, Enzymes, Hypoxia)

The tumor microenvironment (TME) is a unique biochemical environment that can be utilized for the selective delivery of natural products. Tumor tissues are normally characterized by low pH levels, high concentrations of enzymes like matrix metalloproteinases (MMPs) and cathepsins, hypoxia, and redox imbalance. Nano platforms are developed to respond to these conditions, including stimuli-responsive nanoplatforms, which allow for the release of drugs at specific locations.¹²¹ As an illustration, pH-sensitive systems can be used to release their cargo in acidic tumor regions, whereas enzyme-responsive carriers can be used to activate drug release using tumor-associated proteases. The hypoxia-responsive systems are specifically applicable in the treatment of the poorly oxygenated tumor areas that are frequently resistant to standard treatments. Such approaches enhance the stability of natural products in circulation and increase the local activity of the natural products at the site of the tumor¹²² (Table 5).

Besides enhancing selectivity, tumor-responsive delivery systems have also been found to increase therapeutic efficacy and reduce systemic toxicity. These platforms reduce exposure to normal tissues by guaranteeing that the release of drugs is mainly in the tumor microenvironment. It is especially critical in the case of natural products, which might lack stability or show off-target effects.¹²³ Furthermore, by adding several stimuli, like pH and redox responsiveness, additional precision of delivery in complex tumor conditions can be enhanced. The performance of these systems is however, subject to the availability and uniformity of the tumor specific triggers, which again may differ among patients and different regions of the tumor.¹²⁴

Tumor heterogeneity is a significant limitation to stimuli-responsive delivery. Differences in pH, enzyme expression, and oxygen levels may result in unreliable drug release and unpredictable therapeutic outcomes. Most of the systems are optimized in controlled laboratory environments that are not an absolute reflection of the complexity of human tumors.¹²⁵ Hence, although TME-responsive nanoplatforms present a viable solution to enhancing the delivery of natural products, their clinical implementation needs the advancement of multi-responsive systems with the ability to adjust to various tumor histotypes.

Controlled Release and Pharmacokinetics

To achieve effective therapeutic concentrations of natural products and enhance treatment outcomes, controlled drug release is necessary. Nanoplatforms are designed to enable sustained/triggered release, addressing the rapid degradation and clearance often associated with phytoconstituents. Polymeric and lipid-based systems can be used to release drugs gradually, which will enable long exposure at the tumor site, whereas stimuli-responsive carriers can be used to release drugs on demand in response to tumor-specific conditions.¹²⁶ These approaches increase drug stability, decrease the dosing interval, and enhance bioavailability.

As Figure 6 indicates, controlled release directly affects the intracellular drug concentration and treatment efficacy. The pharmacokinetics of nanomedicine-based delivery, such as circulation time, distribution, and clearance, are key determinants of nanomedicine delivery success. Surface modifications can prolong circulation time and decrease immune clearance by PEGylation and biomimetic coatings, permitting higher tumor accumulation.¹²⁷ Biological factors affecting the distribution of nanoparticles, however, include vascular permeability, interstitial fluid pressure and tissue-specific barriers. Although the enhanced permeability and retention (EPR) effect has traditionally been considered a major mechanism of nanoparticle tumor accumulation, its contribution in human tumors is highly variable and often insufficient to fully explain nanoparticle delivery.¹²⁸ The differences between preclinical and clinical pharmacokinetics are still a significant challenge.¹²⁹

Figure 6.

Stimuli-responsive nanoplatforms for precision cancer theranostics. Natural product-loaded nanocarriers are engineered into stimuli-responsive nanoformulations that enhance systemic circulation, tumor accumulation, cellular uptake, and endosomal escape. Triggered by tumor-specific cues such as acidic pH, elevated glutathione (GSH), and matrix metalloproteinases (MMPs), these platforms enable controlled drug release, nuclear targeting, and improved therapeutic efficacy for precision cancer theranostics. Arrows indicate the direction of delivery, cellular internalization, endosomal escape, and triggered release. Colored labels and bold headings denote the major stages of the delivery pathway: drug encapsulation and circulation, tumor microenvironment (TME) accumulation, intracellular controlled release, and therapeutic outcome. pH 5.0 indicates acidic endosomal/tumor conditions; GSH↑ indicates elevated glutathione levels; MMP indicates matrix metalloproteinase activity; EPR indicates the enhanced permeability and retention effect; TME indicates the tumor microenvironment; ECM indicates the extracellular matrix; and NP indicates nanoparticle.

Traditionally, the enhanced permeability and retention (EPR) effect is considered as the main mechanism by which nanoparticles accumulate in tumor tissues, but recent studies indicated that active trans-endothelial transport may be the more important mechanism for the entry of nanoparticles into tumor tissues.¹²⁸ Transcytosis and receptor-mediated transport are mechanisms for the passage of nanoparticles across the vascular barrier, especially in human tumors where passive EPR-mediated accumulation is often heterogeneous and limited. The data underscore the need to develop nanoplatforms based on both active transport and passive targeting mechanisms to ensure efficient delivery and clinical translation.¹³⁰

Critically, there are still difficulties in attaining accurate control of drug release and pharmacokinetics. Early release of the drug during circulation or its incomplete release at the tumor site may lead to a decrease in therapy effect. Moreover, pharmacokinetic characteristics that are observed in animal models do not have a tendency to represent human responses because there are differences in physiology and tumor structure.¹²⁷ Hence, the enhancement of controlled release systems must focus on strengthening the connection between material design and biological insights. Pharmacokinetic optimization of nanomedicines based on natural products is crucial in converting natural-product-based nanomedicines into useful precision cancer theranostics.¹³¹

Immune Modulation and Tumor Heterogeneity

Nano- bio interactions in the tumor microenvironment are vital in the immune response and in defining the effects on therapeutic outcomes. Nanoplatforms can communicate with immune cells, including macrophages, dendritic cells, and T cells, thus affecting anti-tumor immunity. Indicatively, by treating tumor-associated macrophages (TAMs), it is possible to induce their conversion to an anti-tumor (M1) immune phenotype, rather than continuing their pro-tumor (M2) one, which has been shown to promote immune-mediated tumor suppression.¹³² Besides, immune modulation can also be boosted by the delivery of natural products with immunomodulatory effects. Meanwhile, biomimetic and surface-modified nanoplatforms can reduce immune clearance, extend circulation, and enhance tumor accumulation, which shows how these nanoplatforms can be used simultaneously in drug delivery and immune regulation. Heterogeneity in tumors is still one of the biggest challenges to effective treatment. Tumors are made up of heterogeneous populations of cells that differ in genetic profile, receptor expression and in their metabolic state.¹³³ Such diversity influences nanoparticles uptake and results in disproportional drug dispersal in the tumor. Some areas may get low drug exposure, such as areas with thick extracellular matrix or areas with low vascularization. Moreover, resistant subpopulations like cancer stem cells may survive therapy and add to the recurrence of the disease.¹³⁴ All of these make nanomedicine-based therapies less effective. Translational wise, the immune complexity and tumor heterogeneity must be overcome to have a consistent outcome of the therapy.¹³⁵ Multi-functional nanoplatforms integrating targeting, controlled release and immune modulation provide a promising way to overcome these difficulties. Nonetheless, it is still hard to predict immune responses, and provide homogenous delivery of drugs over heterogeneous tumor regions.¹³² As shown in Table 5, nanoplatform design is essential in the integration with patient-specific tumor characteristics to advance natural product-based nanomedicine to precision cancer theranostics.

The recent evidence shows that the formation of protein corona is a dynamic, patient-dependent process, depending on the individual plasma composition, disease condition, age, and therapeutic interventions.¹³⁶ Changes in composition of the corona can lead to changes in the biodistribution, cellular uptake, recognition by the immune system, and therapeutic effects of the nanoparticles.¹³⁷

From a translational point of view, discrepancies between preclinical and clinical results might be partly due to the personalized protein corona: nanoplatforms optimized in standard biological fluids might obtain different corona compositions in cancer patients. Thus, the next generation of precision nanomedicine approaches will need to take into account patient-specific biological parameters through proteomic evaluation, AI-driven prediction capability and patient-specific nanocarrier design to enhance therapeutic efficacy.¹³⁸

Precision Cancer Theranostics

Precision cancer theranostics combines diagnosis and treatment on a single platform to enhance treatment accuracy, response monitoring, and patient-personalized interventions.¹³⁹ The use of bioinspired nanoplatforms is especially appropriate in this strategy, as these nanoplatforms are capable of co-delivering natural products and imaging agents and reacting to tumor-specific environments.¹⁴⁰ This application is significant to natural products that frequently exhibit high biological activity but show little clinical performance due to inadequate targeting and unpredictable effects. Nanoplatforms enable more controlled and adaptive cancer management by integrating therapeutic and diagnostic capabilities.

Diagnostic Imaging (MRI, CT, Fluorescence, Photoacoustic)

For precision cancer theranostics, diagnostic imaging plays a crucial role for imaging tumors, distribution of nanoparticles, and therapeutic response. Bioinspired nanoplatforms are increasingly incorporating both imaging and therapeutic capabilities, providing a platform for simultaneous diagnosis and therapeutic applications.¹⁴¹ There are many techniques used to enhance the detection of tumors and monitor the accumulation of nanoparticles, including MRI, CT, and near-infrared (NIR) fluorescence and photoacoustic imaging.¹⁴²

Multimodal imaging platforms have been developed to combine MRI, CT and optical imaging to overcome the limitations of individual modalities and provide complementary structural and functional information. However, the use of several imaging agents adds system complexity and can influence the stability, biocompatibility and regulatory approval of nanoparticles. Moreover, the majority of the imaging-based nanoplatforms are still at the preclinical level, which requires additional clinical testing of the platform’s clinical utility, reproducibility, and safety before they can be commonly used in precision cancer theranostics.^143,144

Therapeutic Modalities (Chemotherapy, PTT, PDT, Immunotherapy)

One characteristic of precision cancer theranostics is the use of therapeutic integration to deliver and activate various treatment modalities in the most efficient way through bioinspired nanoplatforms. Chemotherapy is still a major treatment technique, and nanocarriers are much better in terms of natural product delivery properties, including solubility, stability, and tumor targeting. As an example, nanoplatforms loaded with curcumin have been shown to have superior intracellular penetration, greater apoptosis and tumor proliferation inhibition as opposed to free drug preparations.¹⁴⁵

Besides chemotherapy, photothermal therapy (PTT) and photodynamic therapy (PDT) can be performed with nanoplatforms, and this treatment mode offers localization and minimally invasive treatment. PDT involves the use of photosensitizers, which are activated by light to produce reactive oxygen species (ROS) that destroy cancer cells, and PTT causes localized hyperthermia, which destroys tumor tissue. These therapies are better facilitated in nanoparticle-based systems through better delivery of photosensitizers, stability, and tumor accumulation.¹⁴⁶ As an example, the nanogels and nanostructures made of curcumin have demonstrated an enhanced production of ROS, enhanced tumor penetration and considerable tumor growth suppression within preclinical models. In addition, the use of nanotechnology with PDT has also been suggested to enhance the effectiveness of the treatment through the enhancement of the intracellular drug concentration and the minimization of the alteration of healthy tissues.¹⁴⁷

Notably, synergistic effects of particle-based treatment arise when several modalities are combined into a single nanoplatform to enhance treatment effectiveness. Numerous studies have demonstrated that chemo- photodynamic and chemo-photothermal processes can be used to a great extent in inhibiting tumor growth and drug resistance as opposed to the single treatment procedures.⁷¹ Indicatively, nanoplatforms have been used in the simultaneous delivery of chemotherapy, PDT, and PTT to tumors where the nanocarriers demonstrated enhanced tumor regression and decreased recurrence when used in preclinical models. Also, nanoplatform-based immunotherapy is being developed as a support mechanism, in which precision in delivering immunomodulatory drugs boosts anti-tumor immunity. Nevertheless, to maximize the multimodal therapies, it is essential to control the treatment parameters, dose, time and interaction between the modalities.¹⁴⁸ Although preclinical results are encouraging, clinical practice remains challenging due to the complexity of the systems, patient variability, and regulatory issues. Thus, the combination of chemotherapy, phototherapy, and immunotherapy into nanoplatforms is a potent yet dynamic solution of precision cancer theranostics.¹⁴⁹

Multifunctional Theranostic Nanoplatforms

Multifunctional theranostic nanoplatforms combine diagnostic and therapeutic functionalities into a single platform, allowing for the conduct of imaging, targeted delivery, and treatment at the same time, as shown in Figure 7. These platforms are intended to integrate various functionalities to enhance treatment precision; these include drug loading, imaging capability, and targeting ligands. As an example, phytochemicals (eg, curcumin, resveratrol, or berberine) can be introduced into hybrid nanoplatforms to serve as chemotherapy agents, photothermal or photodynamic agents and for the delivery of imaging functions (eg, MRI or fluorescence probes).¹⁵⁰ This has been integrated to enable real-time visualization of nanoparticle distribution and directly deliver therapeutic agents to tumor sites to enhance the accuracy of testing and minimize off-target effects.¹⁵¹

Figure 7.

Multifunctional nanocarriers for natural product-based cancer theranostics. Multifunctional nanocarriers integrate natural products, therapeutic agents, targeting ligands, and imaging probes to enable targeted drug delivery, controlled release, and multimodal cancer diagnosis. The black arrows indicate the direction of delivery and release pathways, the blue arrow indicates diagnostic translation toward imaging-based monitoring, the brown arrow indicates therapeutic progression, and the green arrow highlights the connection between nanocarrier advantages and clinical translational challenges. The lightning symbol denotes external light activation used for photothermal or photodynamic therapy. The red starburst symbols represent reactive oxygen species (ROS) generation during photodynamic or related redox-mediated therapies. The pH label indicates stimulus-responsive release in the acidic tumor microenvironment. The icons for MRI and fluorescence represent multimodal imaging and real-time visualization. PTT, PDT, and RDT should be defined in the legend using their full terms as used in the manuscript.

The stability and intracellular delivery of compounds like epigallocatechin gallate (EGCG), quercetin, or thymoquinone can be enhanced by encapsulating them in nanoplatforms. Moreover, the use of more than one therapeutic format in a single system may have synergistic effects.¹⁵² As an example, chemo-photothermal or chemo-photodynamic agents with phytochemicals like curcumin or 2-lapachone have been demonstrated to improve tumor inhibitory effects and promote drug resistance in preclinical models. Selectivity and controlled drug delivery are further enhanced by the use of targeting ligands and stimulus- responsive components that favor a more effective and specific therapeutic process.¹⁵³

Nevertheless, the expansion of functionality also introduces challenges related to design complexity and clinical translation. The use of various phytochemicals and functional components may influence the stability, reproducibility and scalability of nanoparticles. Moreover, communications among various components can affect therapy performance and safety. Translational-wise, the more complex a system is, the more complicated regulatory approval becomes.¹⁵⁴ Thus, although multifunctional theranostic nanoplatforms have immense potential in the delivery of phytochemicals in precision cancer treatment, their effective use needs proper optimization to ensure that multifunctionality is balanced with simplicity, reproducibility, and clinical viability.¹⁵⁵

Although many bio-inspired nanoplatforms have been developed, there are still manufacturing, biological and regulatory challenges facing clinical translation. The nanoparticles with biomimetic systems, for example, are coated with cell membranes and require complex manufacturing process, which can cause high costs and difficult scalability.⁶⁶ Furthermore, the therapeutic effectiveness of preclinical models is underreported, as human tumors are more complex, biologically heterogeneous and stromal than preclinical models. The regulatory challenges are more than the multifunctional theranostic platforms, because these platforms are expected to perform diagnostic and therapeutic tasks, they have to be carefully scrutinized for safety, efficacy, and manufacturing consistency.¹³⁸ To successfully translate natural product-derived precision cancer theranostics into the clinic, these challenges need to be addressed.

Real-Time Monitoring and Personalized Treatment Strategies

Theranostic nanoplatforms feature the functionalities of real-time monitoring of nanoparticle distribution, release of therapeutic agents, and therapeutic response, all integrated with a unique imaging modality such as magnetic resonance imaging (MRI), fluorescence, and photoacoustic imaging. This enables visualization of targeting of tumor, evaluation of treatment efficacy, and early detection of suboptimal drug delivery. These systems, when used in conjunction with molecular profiling, can help guide personalized treatment strategies, optimizing drug selection, dosage, and targeting based on the unique characteristics of each patient’s tumor.^156,157

While promising, clinical use is hindered by variable imaging sensitivity, the intricacy of in vivo drug release monitoring and the additional complexity of multifunctional systems in the regulatory pathway.¹⁵⁸ However, further developments in imaging and new materials at the nanoscale and in the integration of data are continuing to make adaptive, individualized cancer therapy more feasible. Table 6 describes some of the most representative bioinspired theranostic nanoplatforms, their imaging modality, therapeutic functions, advantages and key translation challenges.

Table 6.

Bioinspired Theranostic Nanoplatforms Integrating Phytochemicals, Imaging Modalities, and Therapeutic Strategies in Precision Cancer Treatment

Nanoplatform Type	Phytochemical(s)	Imaging Modality	Therapeutic Modality	Key Functional Advantage	Translational Limitation	Reference
Gold nanoparticles	Curcumin	CT, Photoacoustic	PTT, Chemotherapy	Strong imaging contrast + thermal ablation	Potential accumulation	[128]
Silver nanoparticles	Fisetin	Fluorescence	Chemotherapy, PDT	Anticancer + antimicrobial synergy	Cytotoxicity concerns	[159]
Liposomes	Resveratrol	Fluorescence	Chemotherapy	Improved solubility	Drug leakage	[160]
Polymeric nanoparticles	Berberine	MRI	Chemotherapy	Controlled release	Complex synthesis	[161]
Solid lipid nanoparticles (SLNs)	Kaempferol	Fluorescence	Chemotherapy	Enhanced stability	Low loading capacity	[162]
Nanostructured lipid carriers (NLCs)	Naringenin	Fluorescence	Chemotherapy	Higher drug loading	Formulation complexity	[163]
Mesoporous silica nanoparticles	Camptothecin	Fluorescence, MRI	Chemotherapy, PDT	High drug loading	Biodegradability issues	[164]
Magnetic nanoparticles	Artesunate	MRI	PTT, Chemotherapy	Imaging-guided therapy	Limited clinical validation	[165]
Carbon-based nanomaterials	EGCG	Photoacoustic	PTT, PDT	High surface area	Toxicity concerns	[166]
Quantum dots	Quercetin	Fluorescence	PDT, Chemotherapy	High sensitivity imaging	Heavy metal toxicity	[167]
Dendrimers	Betulinic acid	Fluorescence	Chemotherapy	High loading efficiency	Cytotoxicity	[168]
Nanoemulsions	Gambogic acid	Fluorescence	Chemotherapy	Improved absorption	Physical instability	[169]
Exosome-inspired systems	Curcumin	Fluorescence	Chemotherapy, Immunotherapy	High biocompatibility	Scalability issues	[170]
Cell membrane-coated nanoparticles	Paclitaxel	Fluorescence	Chemotherapy	Immune evasion	Source variability	[171]
Targeted nanoparticles	Sulforaphane	Fluorescence	Chemotherapy, Immunotherapy	Target specificity	Protein corona masking	[172]
Stimuli-responsive nanoparticles	Plumbagin	MRI, Fluorescence	Triggered chemotherapy	Controlled release	Tumor heterogeneity	[173]
Redox-responsive nanoplatforms	Thymoquinone	Fluorescence	Chemotherapy	Intracellular targeting	Redox variability	[174]
pH-responsive nanoparticles	Oridonin	Fluorescence	Chemotherapy	Tumor-specific release	pH variability	[175]
Hybrid nanoplatforms	Curcumin + β-lapachone	MRI, Fluorescence	Chemo, PTT, PDT	Multi-modal synergy	High complexity	[176]
Multi-responsive nanoplatforms	Celastrol	MRI, Photoacoustic	Chemo, PTT, PDT	Adaptive precision therapy	Regulatory challenges	[177]
Metal–organic frameworks (MOFs)	Apigenin	Fluorescence	Chemotherapy, PDT	High porosity	Stability issues	[178]
Polymer–lipid hybrid nanoparticles	Honokiol	MRI, Fluorescence	Chemotherapy	Improved stability	Manufacturing complexity	[179]

Clinical Translation, Challenges, and Future Perspectives

Adapting bioinspired nanoplatforms in the area of precision cancer theranostics is a significant challenge of moving laboratory-scale innovation to clinical use. Although there has been a lot of progress in enhancing the delivery and efficacy of natural products, barriers that exist in relation to safety, regulatory and manufacturing need to be addressed to translate this into clinical practice. These issues have an interlinking relationship and have to be addressed in order to come up with reproducible, scalable and clinically effective nanomedicine systems.¹⁵⁵

Safety, Toxicity, and Biocompatibility (Natural Product-Based Nanoplatforms)

The clinical translation of natural product-based nanoplatforms is based on safety and biocompatibility of the nanoparticle structure in precision cancer theranostics. There is established evidence of anticancer, antioxidant and anti-inflammatory effects of phytochemicals like curcumin, resveratrol, quercetin, epigallocatechin gallate (EGCG) and berberine, although their application in the clinical setting is often constrained by low systemic bioavailability, rapid metabolism and insolubility.¹⁸⁰ Nano-encapsulation has been demonstrated to enhance these properties greatly by providing better stability, resisting degradation, and extending the circulation time. Indicatively, compared to conventional curcumin nanoformulations, nanoparticles that are loaded with curcumin have been shown to exhibit better plasma half-life and tumor accumulation, and resveratrol and EGCG nanoformulations have been shown to have better cellular uptake and sustained release, resulting in better therapeutic efficacy in preclinical models.^181,182

Another effect of nanoformulation on phytochemical toxicity is the optimization of targeted conformation and limitation of the systemic exposure of the phytochemicals. Nanocarriers based on berberine and quercetin have demonstrated increased cytotoxicity following cancer cells and reduced toxicity on normal ones because of an improved tumor-specific accumulation.¹⁸³ Likewise, nanoformulations of thymoquinone, genistein and apigenin have also shown selective anticancer effects at low off-target effects in animal models. These results indicate that nanoplatforms can continue to increase the therapeutic window of phytochemicals by enhancing efficacy and reducing adverse effects. Besides, lipid-based and polymeric nanocarriers enhance biocompatibility by decreasing the direct contact of free phytochemicals with healthy tissues.¹⁸⁴

The safety of these systems is, however, not limited to the phytochemical but also to the carrier design and physicochemical properties. Particle size, the surface charge, and the composition of the material are some of the factors that affect biodistribution and toxicity. As an example, most biodegradable polymeric and lipid-based systems are easily tolerated, but inorganic nanomaterials can be deposited in the liver and spleen, which could be toxic over time.¹⁸⁵ Moreover, the formation of a protein corona can change the identity of nanoparticles and modify immune recognition and may cause unpredictable biological responses. It has also been demonstrated that the surface charge is a two-sided situation, that is, positively charged nanoparticles can increase uptake in cellsand cause cytotoxicity and hemolytic effects.¹⁸⁶

Translationally, the majority of safety information available on nanoplatforms based on phytochemicals is from short-term in vitro and animal research, which does not necessarily accurately represent human physiology. There is a lack of information on chronic toxicity, repeated dosing and chronic biodistribution.¹⁸⁷ Moreover, the inconsistency of safety across studies may be due to variability in the formulation methods. Thus, phytochemicals, ie luteolin, kaempferol, silibinin and andrographolide provide a good background to such safer nanomedicine systems; however, detailed and standardized assessment of the active compounds, as well as their carriers is necessary.¹⁸⁸ The next areas of nanoplatform translation to be investigated in the future are long-term safety profiling, reproducibility, and clinically rational validation to guarantee safe translation of natural product-based nanoplatforms in precision cancer theranostics.¹⁸⁹

Clinical Progress and Regulatory Considerations

Strong preclinical results of natural product-based nanoplatforms have not been translated in clinical studies. Although some nanomedicine systems, especially lipid and polymer-based systems, have been developed to clinical applications, the majority of phytochemical-loaded nanoplatforms are in preclinical stages of development.¹⁹⁰ One of the largest problems is the discrepancy between the efficacy in the laboratory and clinical practice, and the variability in tumor biology and patient response is influenced by these variations in therapeutic outcome. Moreover, with the growing complexity of the systems in multifunctional platforms, reproducibility and standardization become more challenging.¹⁹¹

These systems are complicated to regulate because many are combination products, in which the drug and device properties must be evaluated. Agencies like the U.S. Food and Drug Administration, as well as the European Medicines Agency insist on specific physicochemical characterization including particle size, surface characteristics, stability, and drug release characteristics. Good Manufacturing Practice (GMP) is obligatory to maintain uniformity, especially on plant-derived compounds, whose variability of raw material can influence quality.¹⁹²

The existing regulatory models focus on the Quality by Design conceptualization, in which the critical quality attributes and process parameters are outlined at an early stage to provide reproducibility. Besides this, the pharmacokinetic, biodistribution, and toxicity studies should be conducted extensively to determine the nanoparticle behavior in vivo.¹⁹³ Certain consideration is made for factors concerning nanoparticles, including the formation of protein coronas, immune responses, and long-term deposition, which can affect the safety and effectiveness.¹⁹⁴

Translational-wise, regulatory acceptance hinges on demonstrating a clear clinical advantage over the standard formulation. This involves increased effectiveness, decreased toxicity, or increased patient compliance. In the case of theranostic systems, therapeutic and diagnostic elements must be approved, making regulation more intricate. Thus, a proper design of nanoplatforms according to regulatory standards, standardization, and the creation of effective clinical evidence should be viewed as key steps to the clinical-level development of natural product-based nanomedicine.^195,196

Scalability and Manufacturing Challenges

One of the essential obstacles preventing the transfer of natural product-based nanoplatforms between laboratory studies and patient care is scalability. Most systems are optimized under controlled conditions, which are hard to scale to large levels. Changes in the synthesis parameters may cause inconsistencies in particle size, morphology, and drug loading. The problem is further exacerbated by the fact that phytochemicals such as curcumin, resveratrol, berberine, and quercetin have physicochemical characteristics (eg, insolubility and instability) that require specific formulations.¹⁹⁷ Moreover, natural variations in plant-derived compounds, including variations in the extraction yield and purity of compounds such as EGCG, luteolin, and kaempferol, may influence the stability of the formulation and the in vitro product quality.¹⁹⁸

The production issues are even more severe in multifunctional nanoplatforms that use multiple phytochemicals or integrated therapeutic systems. Indicatively, co-delivery systems that incorporate compounds like thymoquinone, genistein and apigenin must be optimized keenly to attain consistency in encapsulation and their release. Likewise, incorporation of hydrophobic phytochemicals like 2 -lapachone, celastrol or gambogic acid into nanocarriers requires careful control of formulation factors to prevent aggregation or early release.¹⁹⁹ The biomimetic systems are enhanced even further, as introducing biological materials and the use of phytochemicals like honokiol or andrographolide provide even more variability and standardization issues.²⁰⁰

To solve these problems, there is growing interest in more advanced manufacturing strategies, such as microfluidics, continuous-flow synthesis, and controlled self-assembly, to enhance reproducibility. These methods provide greater control over nanoparticle formation and drug loading, especially for structurally diverse phytochemicals. Nevertheless, it remains difficult to scale these technologies to industrial manufacturing particularly when it is necessary to work with numerous active compounds of varied physicochemical properties. Moreover, it is important to store them in a stable condition since there are phytochemicals which are light sensitive, temperature sensitive, and oxidized.^201,202

Effective production must balance formulation complexity with reproducibility and scalability. Production can be enhanced by making the nanoplatforms easier to design and retain therapeutic functionality. Phytochemical sources, extraction procedures and formulation procedures should also be standardized to guarantee uniform product quality. Thus, beyond being a technical necessity, the process of addressing scalability and manufacturing is also an important step towards enabling reliable and clinically translatable natural product-based nanomedicine systems towards precision cancer theranostics.²⁰³

Emerging Directions (AI-Driven Design, Personalized Nanomedicine, Green Synthesis)

The development of natural product-based nanoplatforms is evolving due to emerging strategies that address the drawbacks of variability, complexity, and translation. AI and machine learning are being used to streamline the design of nanocarriers for phytochemicals. Such tools can forecast the relationships between physicochemical characteristics, including solubility, stability, and molecular interactions, and nanoparticle functionality. In structurally diverse phytochemicals (eg, curcumin, EGCG, berberine, and celastrol), AI-based models are applicable to select an appropriate carrier, optimize drug loading and predict release behavior.²⁰⁴ This minimizes trial-and-error methods, which are empirical and speeds up the formulation process. Nevertheless, the quality of these models is affected by the quality of datasets that are of high quality, which are yet to be available for many plant-derived compounds.²⁰⁵

Another promising direction is personalized nanomedicine, in which the nanoplatforms are designed based on patient-specific tumor features. Phytochemicals like resveratrol, quercetin, and genistein are multi-target.²⁰⁶ That is why they can be used in individualized therapy because treatment can be personalized depending on tumor subtype, receptor expression, and microenvironmental conditions. Indicatively, hypoxia-reacting systems can be more effective in tumors that have aggressive features, whilst immune-modulating phytochemicals like curcumin or andrographolide can be chosen for tumors with high levels of immunosuppressive characteristics. Nonetheless, patient variability and the difficulty of incorporating molecular profiling and nanoplatform design are still major issues.²⁰⁷

Green synthesis is also becoming a popular method for the production of nanoplatforms based on plant-derived compounds, owing to its sustainability. Phytochemicals also may serve as reducing and stabilizing agents in the process of nanoparticle production, and thus, it is possible to produce metallic nanoparticles without toxic substances.²⁰⁸ Flavonoids (eg, quercetin, kaempferol) and polyphenols (eg, EGCG) compounds have been utilized to develop biocompatible nanoparticles with less adverse environmental impact. Green synthesis can also increase biocompatibility by reducing residual toxic reagents and improving sustainability. Nevertheless, particle size, morphology and reproducibility are difficult to control in such systems, particularly in larger-scale production.²⁰⁹

Critically, though these new directions have great potential, they must be carefully validated before being integrated into clinical practice. The AI-driven design needs to be justified by experimental and clinical data, personalized nanomedicine needs to have solid diagnostic and profiling infrastructure, and any green synthesis should be able to achieve reproducibility that is equal to other technologies.²¹⁰ Hence, the development of nanoplatforms based on natural products in the future will rely on the integration of technological advancement and standardized approaches with clinical significance. All these approaches offer a way forward to a more efficient, sustainable, and patient-specific system of nanomedicine in precision cancer theranostics.²¹¹

Why Nanomedicine Fails in Clinical Oncology

Although nanomedicine has shown great promise in preclinical studies for cancer treatment, its clinical success in oncology remains low. The overestimation of the enhanced permeability and retention (EPR) effect is among the main causes for passive tumor targeting. Although EPR is always reproducible in small animal models, its size and accuracy in human tumors are extremely variable because of variations in the structure of the vascular system, interstitial pressure, and tumor physiology. This leads to nanoparticles being accumulated in clinical situations, usually at much lower and less predictable levels than anticipated. The other major obstacle is the heterogeneity of tumors that is interpatient and intratumoral.²¹² Differences in vascularization, density of the extracellular matrix, hypoxia and expression of receptors result in certain uneven distributions of nanoparticles and uneven drug exposures between tumor regions. As a result, in cases where partial tumor targeting is attained, some resistant subpopulations may not have been adequately addressed, leading to failure in treatment and reoccurrence of the disease. Also, the pharmacokinetics in preclinical models and human systems are significantly different. Optimized nanoplatforms when in controlled experimental conditions can be found to have good circulation time, biodistribution, and release characteristics, but such characteristics do not always apply in human physiology.^213,214 Immune recognition, protein corona formation, and organ-level clearance variations also complicate the reliable prediction of in vivo behavior, thus restricting the applicability of preclinical results. Lastly, regulatory complexity can be viewed as a significant challenge to clinical translation. Several nanomedicine systems can be considered combination products, in which both drug and device aspects should be evaluated simultaneously. Multifunctional platforms in which targeting ligands, imaging agents, and therapeutic payloads are combined make manufacturing difficult and standardization, quality control, and large-scale production difficult.²¹⁵ Also, the absence of standardized regulatory measures and long-term safety data is another factor slowing clinical approval. In summary, these restrictions emphasize that technological progress will not be enough to achieve success in translation. The variation in tumor biology, the development of better predictive preclinical models, the ease of designing a nanoplatform, and adherence to regulatory needs are the necessary steps toward the realization of the clinical potential of natural product-based nanomedicine in precision cancer theranostics.²¹⁶

Discussion

Despite the increased solubility, stability and tumor accumulation of natural products with the aid of nanoplatforms, these benefits do not always translate into increased survival rates or long-term treatment response. One of the factors is intratumoral heterogeneity that causes uneven nanoparticle penetration and exposes resistant tumor areas to insufficient exposure. Moreover, pharmacokinetic advantages in preclinical models do not frequently correlate with human findings since they overestimate the delivery efficiency and reduce tumor biology.²¹⁷ These restrictions imply that the delivery improvement as a single measure should not be viewed as a sign of the translational success.²¹⁸

The present review presents a combined model of natural products, nanoplatform engineering and precision cancer theranostics. Although phytochemicals show high anticancer effects due to their ability to induce apoptosis, ROS change, and signaling, a majority of the data is preclinical and tends to be based on concentrations that are not attainable in vivo. This is also a major drawback: mechanistic promise is not always converted into clinical efficacy, and there is a need to develop pharmacokinetically relevant assessment plans.

Nanoplatforms are suggested to address all of these limitations by enhancing delivery, stability, and targeting. Nevertheless, their clinical effect remains unclear. Most of these systems are based on assumptions such as the EPR effect, which can vary widely across human tumors and has only been tested in models. Consequently, better delivery does not necessarily result in better therapeutic outcomes. This is indicative of a wider problem in the field: excessive dependence on preclinical models, which lack the ability to model tumor heterogeneity and variation in patients.^219,220

The critical gap is the lack of biomarker-based use of natural products. The majority of phytochemicals are not used selectively, with some exceptions, which limits their use in precision oncology. Similarly, although systems that combine imaging and therapy have been termed multifunctional theranostic systems, the growing complexity poses challenges to reproducibility, scalability, and regulatory approval. This generates a major trade-off in which, as the functionality increases, the translational feasibility decrease.^221,222 In general, the paradigm is shifting toward translational validation rather than mechanistic exploration. The future development needs to focus on priorities in clinically relevant models, biomarker-driven approaches and harmonized nanoplatform design.²²³ Thus, despite great potential of natural product-based nanomedicine, the success of this nanomedicine in the clinic requires a transition towards evidence-based, patient-specific and scalable solutions.²²⁴

Case Study

Case Study 1: Natural Compound-Based Carrier-Free Nanoparticles in Cancer Therapy

Carrier-free nanoparticles that are based on natural products have become a prospective platform in improving chemo-photodynamic cancer therapy by integrating inherent therapeutic effects of bioactive compounds with effective nanodelivery (Figure 8). These nanoparticles can be made by noncovalent self-assembly interactions, such as hydrophobic interactions, π-π stacking, hydrogen bonding, and electrostatic interactions, as shown in Figure 8i, thereby enhancing drug loading, biocompatibility, and tumor targeting, and eliminating carrier-related toxicity. Along these lines, Figure 8ii shows the self-assembly of genistein and chlorin e6 (Ce6) into GC nanoparticles, where genistein prevents glucose uptake, thereby causing tumour starvation, whereas Ce6 generates reactive oxygen species (ROS) upon laser irradiation, leading to synergistic antitumor activity. Following this approach, Figure 8iii reveals OC nanoparticles composed of oleanolic acid and Ce6, which also enhance tumor penetration and ROS-mediated cytotoxicity under light and ultrasound stimulation. Similarly, Figure 8iv also emphasizes 10-hydroxycamptopherin (HCPT)-Ce6 nanorods, which exhibit enhanced stability, sustained release, and improved chemo-photodynamic therapeutic activity. Together, these correlated illustrations show that natural compounds may be rationally incorporated into carrier-free nanoplatforms to deliver them more specifically to tumors, with less systemic toxicity and greater anticancer efficacy.¹⁵³

Figure 8.

Carrier-free nanoplatforms derived from bioactive natural products for synergistic chemo–photodynamic cancer therapy. (i) Design strategy of carrier-free nanoparticles via self-assembly of natural products and photosensitizers through noncovalent interactions for improved tumor-targeted PDT. (ii) Genistein/Chlorin e6 (GC) nanoparticles. (A) Nanoparticle formation by co-precipitation. (B) GLUT1 inhibition, starvation therapy, ROS generation, and hypoxia relief. (C) In vivo antitumor efficacy (tumor growth, excised tumors, tumor weight). (iii) Oleanolic acid/Chlorin e6 (OC) nanoparticles. (A) Self-assembly of OA and Ce6. (B) EPR-mediated tumor targeting, ROS generation, apoptosis, and combined chemo/sono/PDT. (C) Therapeutic efficacy evaluation with tumor inhibition analysis. (iv) HCPT/Chlorin e6 nanorods. (A) Co-assembly of HCPT and Ce6 nanorods. (B) Tumor targeting, sustained drug release, laser-triggered ROS generation, and PDT-mediated cell death. (C) In vivo antitumor efficacy and tumor inhibition assessment.¹⁵³ *P < 0.05; **P < 0.01; ***P < 0.001; ns, not significant (P > 0.05). Red dotted circle indicates the highlighted tumor sample/group of interest exhibiting complete tumor suppression. (Copyright Elsevier, Wang et al 2024).

Case Study 2: Nanoparticle-Based Cancer Theranostics as a Transformative Strategy in Precision Oncology

Poor tumor selectivity, systemic toxicity, multidrug resistance and lack of real-time monitoring of treatment response are some of the factors that hinder cancer treatment. This case study identifies nanoparticles as versatile systems that can address these shortcomings by targeting the tumor, increasing bioavailability, improving tumor localization, and reducing off-target toxicity. Alongside the use of nanoparticles as drug carriers, they may be used as diagnostic and imaging agents, thus facilitating the creation of theranostic platforms that enable more specific and individualized cancer treatment. Both organic and inorganic nanoparticles mentioned in the article show great potential to increase the effectiveness of therapy and reduce harm to healthy tissues. Figure 9 effectively supports this idea by demonstrating the practical uses of nanoparticles in cancer as theranostic agents. The diagnostic capabilities of nanotechnology are illustrated in Figure 9i, where PEGylated ZnGa 2O 4:Cr 3+ nanocubes have been used as persistent luminescence tumor imaging probes. Continuing on this, Figures 9ii–iv also reveal how nanoparticles could be designed into multifunctional systems which combine tumor imaging, targeted delivery and therapeutic intervention in one platform. Collectively, these illustrations highlight that nanoparticles undergo transformation to become not just traditional drug carriers but highly sophisticated image-guided and treatment-responsive nanoplatforms, providing a promising avenue for precision oncology and minimally invasive cancer treatment.¹⁹

Figure 9.

Representative nanoparticle-based theranostic systems for cancer diagnosis and treatment. i) PEGylated ZnGa₂O₄³⁺ nanocubes for persistent luminescence imaging. (a) TEM image of nanocubes. (b) Persistent luminescence spectrum. (c) Luminescence decay profile. (d) In vivo tumor imaging. (e) Ex vivo biodistribution analysis. (ii) Folate receptor-targeted multifunctional nanoparticles. Self-assembled PEG/PCL nanoparticles carrying paclitaxel and shBCL-2 plasmid, showing folate receptor-mediated uptake, endosomal escape, intracellular release, and targeted cancer therapy. (iii) Integrated theranostic nanoparticles. (A) Serial fluorescence imaging. (B) Tumor growth analysis. (C) Survival analysis. (D) Fluorescence staining. (E) Histopathology staining. (F) Immunohistochemical staining confirming therapeutic efficacy. (I) Control; II: 6 Gy; III: Au@Tat-R-EK; IV: Au@Tat-I-EK + 6 Gy; (V) Au@Tat-R-EK + 6 Gy. *P < 0.05; **P < 0.01. (iv) BODIPY-based nanoparticle photodynamic immunotherapy. (A) Synthesis of BODIPY photosensitizer: (i) BDP, (ii) BDP-I, (iii) BDP-I-N. (B) Nanoparticle fabrication: (i) self-assembly, (ii) surface amination, (iii) anti-PD-L1 conjugation. (C) Targeted uptake with NIR-triggered ^1O₂ generation for PDT. (D) Combined photodynamic immunotherapy inducing tumor destruction and T-cell activation.¹⁹ (Copyright Elsevier, Raheem et al 2023).

Conclusion

In this review, a framework that integrates natural products and bioinspired nanoplatforms is presented to enable precision cancer theranostics. It emphasizes that the therapeutic benefits of phytochemicals cannot be fully exploited in their free form, but can be improved by rational nanotechnological design. Nanoplatforms transform natural products into potential building blocks of contemporary precision oncology by enhancing delivery efficiency, enabling fine-tuned release, and providing multi-modal functionality.

One of the major developments described in this publication is the incorporation of both diagnostic and treatment features in the same platforms, contributing to real-time monitoring and adaptive approaches to treatment. This systems-level therapy is no longer traditional therapy but rather coordinated cancer therapy, in which the administration of drugs, localization of tumor and assessment of whether the therapy is effective are interrelated. This integration is especially vital to treat tumors with full complexity and precision in treatment.

The future of this field is based on the link between innovation and clinical relevance. The development of this will involve the elucidation of standardized design approaches, reproducibility of manufacture, and testing in clinically representative models. Moreover, the use of biomarker-directed methods and tumor uniqueness will be critical in order to maximize the power of precision theranostics.

Finally, bioinspired natural product nanoplatforms are an effective yet developing approach to cancer therapy. The gap between experimental innovation and clinical applicability will be bridged, leading to the successful translation of these innovations and providing more impactful, specific, and personalised cancer treatment.

Funding Statement

No funding agency is acknowledged.

Availability of Supporting Data

All data will be provided in the manuscript file.

Abbreviations

AI, Artificial Intelligence; CT, Computed Tomography; ECM, Extracellular Matrix; EGCG, Epigallocatechin Gallate; EMA, European Medicines Agency; EPR, Enhanced Permeability and Retention; FDA, Food and Drug Administration; GMP, Good Manufacturing Practice; GSH, Glutathione; HER2, Human Epidermal Growth Factor Receptor 2; IFP, Interstitial Fluid Pressure; MMPs, Matrix Metalloproteinases; MRI, Magnetic Resonance Imaging; NIR, Near-Infrared; NLCs, Nanostructured Lipid Carriers; NPs, Nanoparticles; PDT, Photodynamic Therapy; PEGylation, Polyethylene Glycol Surface Modification; PI3K/Akt, Phosphoinositide 3-Kinase/Protein Kinase B; PK, Pharmacokinetics; PK–PD, Pharmacokinetic–Pharmacodynamic; PTT, Photothermal Therapy; RBC, Red Blood Cell; ROS, Reactive Oxygen Species; SLNs, Solid Lipid Nanoparticles; TAMs, Tumor-Associated Macrophages; TME, Tumor Microenvironment.

Ethical Approval and Consent to Participate

No ethical approval was required in this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that there are no conflicts of interest related to the publication of this article.