Nanoparticle delivery of Chinese medicine monomers for remodeling the colorectal cancer immune microenvironment

Abstract

Aim

The colorectal cancer (CRC) microenvironment is typically “cold,” characterized by sparse immune infiltration and complex immunosuppressive networks, which limits the efficacy of immune checkpoint blockade (ICB). Traditional Chinese medicine (TCM) active monomers (such as curcumin, resveratrol, paclitaxel, and ginsenosides) possess inherent advantages in multi-target and multi-pathway anti-tumor immune regulation, but their clinical translation is hindered by low solubility, short half-life, and insufficient targeting. The purpose of this review is to summarize the recent progress of utilizing nanoparticle formulations of TCM monomers to reshape the CRC immune microenvironment and overcome these delivery obstacles.

Materials and methods

Relevant literature on the nano-delivery of TCM monomers for CRC immunotherapy was systematically searched across major databases including PubMed, Web of Science, and CNKI, using keywords such as “colorectal cancer,” “tumor microenvironment,” “nanoparticle,” “traditional Chinese medicine,” and “active monomers”. Relevant articles were screened, analyzed, and reviewed.

Results

Nanoparticle-delivered TCM monomers play a promising role in reshaping the CRC microenvironment through mechanisms classified into three dimensions: (1) “igniting” anti-tumor immunity by inducing immunogenic cell death (ICD), pyroptosis, and cGAS-STING activation; (2) improving the innate immune “soil” by reprogramming tumor-associated macrophages (TAMs) and promoting dendritic cell (DC) maturation; and (3) “normalizing” physical and chemical barriers by alleviating hypoxia, regulating abnormal metabolism, and remodeling the tumor stroma.

Conclusion

Nano-delivery technologies serve as a promising strategy to unlock the therapeutic potential of TCM monomers in CRC treatment. Despite significant preclinical progress, translational challenges remain, including long-term nanomaterial biosafety, scalable manufacturing barriers, and the limitations of traditional animal models in capturing human CRC immune heterogeneity. Future integration of materials science, pharmaceutics, and immunology may facilitate the development of smart nano-formulations, overcoming these bottlenecks and opening new avenues for combination immunotherapy in advanced CRC.

Graphical Abstract

Introduction

Colorectal cancer (CRC) remains the third most commonly diagnosed malignancy and the second leading cause of cancer-related death worldwide [1]. Despite the efficacy of screening, prognosis remains poor for patients diagnosed at an advanced stage, particularly those with metastatic disease [2–4]. Immune checkpoint blockade (ICB) has achieved breakthrough success in several solid tumors, but the majority of CRC patients—especially those with microsatellite‑stable (MSS) tumors—show extremely low response rates [5, 6]. This resistance is largely attributable to the fact that CRC often presents as an “immunologically cold” tumor, characterized by sparse immune cell infiltration and a highly heterogeneous tumor microenvironment (TME) that establishes a robust immunosuppressive network [7–10]. Therefore, effectively breaking TME immune tolerance and converting “cold” tumors into “hot” ones has become a critical bottleneck in CRC immunotherapy.

This therapeutic refractoriness is orchestrated by a multilayered immunosuppressive TME [11]. In MSS CRC, resistance to immunotherapy arises from at least three barriers. First, limited release of tumor‑associated antigens (TAAs) fails to prime dendritic cells (DCs), leading to immunological ignorance [12–14]. Second, abundant infiltration of immunosuppressive immune cells—particularly M2‑polarized tumor‑associated macrophages (TAMs), myeloid‑derived suppressor cells (MDSCs), and regulatory T cells (Tregs)—constructs a profound immunosuppressive shield [15–17]. Third, physical and metabolic hurdles, such as the dense extracellular matrix (ECM) formed by cancer-associated fibroblasts (CAFs) and the dysregulated glucose/lactate metabolism (the “Warburg effect”), physically sequester T cells and impair their cytotoxic functions [18, 19]. Consequently, blocking a single checkpoint is insufficient; remodeling the TME both physically and metabolically is urgently needed to restore effective antitumor immunity.

In the search for TME modulators, natural products derived from Traditional Chinese Medicine (TCM) have emerged as a treasure trove of bioactive candidates [20, 21]. Unlike conventional chemotherapeutics that typically act on a single well-defined target, TCM monomers such as curcumin, resveratrol, shikonin, and ginsenosides can interact with multiple signaling pathways, a property that may be advantageous for modulating the complex TME [10, 22–24]. Emerging evidence suggests these agents can induce immunogenic cell death (ICD), repolarize TAMs, and normalize tumor vasculature [19, 22, 25]. However, the clinical translation of these promising monomers is severely hindered by their intrinsic physicochemical limitations: poor water solubility, rapid renal clearance, low bioavailability, and non-specific biodistribution. Many free Chinese medicine monomers are limited by insufficient systemic exposure rather than a classical narrow safety margin. In patients with advanced colorectal cancer, oral curcumin at 3.6 g/day produced plasma concentrations of only approximately 10 nmol/L, despite no dose-limiting toxicity. Resveratrol also undergoes rapid metabolism, with an oral bioavailability of unchanged resveratrol below 1%; even after a 5 g oral dose, its peak plasma concentration was only approximately 539 ng/mL. These findings indicate that limited systemic tumor exposure is a major limitation, providing a pharmacokinetic rationale for nanoparticle-based delivery [26–29]. Nanotechnology can markedly improve the systemic exposure of Chinese medicine monomers. A nanoparticle curcumin formulation increased Cmax by approximately 18.4–20.5-fold and AUC by approximately 35.9–42.6-fold. However, PK gains should not be equated directly with therapeutic-window expansion without efficacy and toxicity dose data. Overall, nanoplatforms improve monomer exposure and tumor delivery [30, 31].

Compared with conventional TME modulators, such as immune checkpoint inhibitors or synthetic small-molecule agents that generally target a single signaling pathway, Chinese medicine monomers exhibit intrinsic multi-target and multi-pathway regulatory activities. They can simultaneously modulate tumor cells, immune cells, inflammatory signaling, and metabolic reprogramming, making them particularly suitable for the highly heterogeneous CRC immune microenvironment [32, 33]. However, their poor bioavailability and limited tumor accumulation substantially restrict their therapeutic efficacy. Nanoparticle-based delivery systems provide an effective strategy to overcome these limitations by improving pharmacokinetics, tumor targeting, and controlled drug release [34, 35]. Therefore, this review specifically focuses on nanoparticle-delivered Chinese medicine monomers because of their unique advantages for comprehensive immune microenvironment remodeling.

Rather than providing direct cytotoxicity alone, nanoparticle-delivered Chinese medicine monomers offer a complementary strategy for coordinated regulation of multiple immunosuppressive mechanisms within the CRC microenvironment. Diverse nanoplatforms—liposomes, polymeric micelles, metal‑organic frameworks (MOFs), and biomimetic cell membrane‑coated nanoparticles—can improve the pharmacokinetic profile and tumor delivery of TCM monomers [36–38]. More importantly, “smart” nanocarriers can be functionalized to achieve precise tumor targeting and responsive drug release triggered by TME cues such as acidity, enzymes, or reactive oxygen species [37 ].Baicalein has also been shown to suppress cancer stemness in microsatellite instability CRC by targeting AHCY, providing a potential molecular target for future delivery strategies [39]. In principle, this may increase TME accumulation of TCM monomers, enhancing immunomodulatory effects while reducing systemic toxicity [40]. Furthermore, nanotechnology facilitates the co-delivery of TCM monomers with chemotherapeutics or immunoadjuvants, enabling synergistic strategies that convert “cold” tumors into “hot” ones [41].

Although several reviews have discussed nanomedicine for CRC, most focus on direct cytotoxicity or general drug delivery. A comprehensive synthesis specifically dissecting the molecular mechanisms by which nanoparticle-formulated TCM monomers remodel the immune microenvironment is currently lacking [42]. This paper will delve into three core dimensions: first, exploring strategies to “ignite” anti-tumor immunity by inducing ICD, pyroptosis, and activating the cGAS-STING pathway; second, analyzing methods to “reprogram” the innate immune soil by targeting TAMs and DCs; and third, elucidating the mechanisms of “normalizing” the physical and metabolic microenvironment of the tumor bed through reversing hypoxia, regulating aberrant metabolism, and dismantling stromal barriers. This review aims to provide a systematic theoretical foundation and forward-looking strategies for the development of novel, highly efficient nano-immunotherapies for colorectal cancer based on Chinese medicine monomers (Fig. 1).

Fig. 1.

A triple-dimensional strategy for remodeling the colorectal cancer immune microenvironment via nanoparticle-delivered tcm monomers

Characteristics and therapeutic vulnerabilities of the immunosuppressive microenvironment in CRC

To understand how nanoformulated TCM monomers remodel the CRC microenvironment, one must first appreciate the key immunosuppressive components and their functional properties. This section outlines the major cellular populations, signaling and metabolic pathways, and physical barriers that collectively establish immune evasion in CRC. Importantly, each of these features represents a therapeutic vulnerability that can be selectively targeted by TCM monomers delivered via nanocarriers—a theme that will be further elaborated in the subsequent sections on “igniting,” “reprogramming,” and “normalizing” strategies.

Core immunosuppressive cell populations

Within the CRC microenvironment, the dysregulation of both innate and adaptive immune cells orchestrates a potent immunosuppressive network [43]. TAMs are among the most abundant infiltrating leukocytes. Under the influence of tumor-derived factors, TAMs predominantly exhibit an M2-like polarized phenotype [43, 44]. By secreting factors such as IL-10, TGF-β, and VEGF, they suppress anti-tumor inflammatory responses while promoting angiogenesis and matrix remodeling [45]. Importantly, TCM monomers such as curcumin and ginsenosides have been shown to repolarize M2 TAMs toward an M1-like phenotype, offering a direct strategy to reverse this immunosuppressive cell population (see Sect. 4). MDSCs constitute another hallmark of immune evasion in CRC [46]. These immature myeloid cells deplete arginine within the microenvironment through the overexpression of Arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS), resulting in T cell proliferation arrest and the downregulation of the T-cell receptor (TCR) ζ-chain. Furthermore, Tregs are significantly enriched in CRC tissues; they directly impede the cytotoxic activity of effector T cells via contact-dependent mechanisms and the secretion of inhibitory cytokines [47]. Under the concerted action of these cell populations, CD8⁺ cytotoxic T lymphocytes (CTLs) are frequently rendered into an “exhausted” state [48]. This state is characterized by the high expression of inhibitory receptors such as PD-1, TIM-3, and LAG-3, accompanied by a loss of prolifer ative capacity and a significant reduction in perforin and granzyme secretion, ultimately leading to the failure of effective tumor elimination [49]. Beyond conventional myeloid and lymphoid populations, innate lymphoid cells are emerging as important regulators of tumor immunity. In particular, group 2 innate lymphoid cells (ILC2s) exhibit context dependent functions in cancer [50]. Although type 2 immune responses have traditionally been associated with tissue repair and tumor promotion, recent evidence indicates that ILC2s may also contribute to cancer immunosurveillance by coordinating eosinophils, dendritic cells, and T-cell responses. Their functional phenotype is shaped by local cytokines, metabolic conditions, and stromal signals, suggesting that ILC2s may either support or restrain tumor progression [51]. However, whether nanoparticle-delivered Chinese medicine monomers can directly regulate ILC2 activation or plasticity in colorectal cancer remains largely unexplored. Incorporating ILC2s into future studies may therefore broaden the current myeloid-centered framework and reveal additional mechanisms of immune microenvironment remodeling.

Key signaling pathways and metabolic characteristics

Cellular interactions within the TME are governed by complex intracellular signaling pathways and metabolic reprogramming. The NF-κB and STAT3 pathways serve as a critical nexus linking inflammation and tumorigenesis. In CRC, the persistent activation of these pathways not only sustains tumor cell proliferation and survival but also induces the expression of various immunosuppressive factors, thereby establishing a pro-tumorigenic inflammatory loop [52]. Natural products such as resveratrol and shikonin have been reported to inhibit NF‑κB/STAT3 activation, thereby alleviating immunosuppression—an effect that can be potentiated by nanoparticle delivery. The TGF-β signaling pathway acts as a pivotal driver of “immune exclusion” in CRC. Elevated levels of TGF-β not only directly inhibit the functions of NK cells and CTLs but also drive the activation of fibroblasts, fostering the formation of a “cold tumor” phenotype [53].

Counterbalancing these immunosuppressive mechanisms, yet often remaining silenced in CRC, is the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) signaling pathway [54]. As a central hub for innate immune sensing, the effective activation of the cGAS-STING pathway enables the recognition of abnormal tumor-derived DNA within the cytoplasm, subsequently inducing the potent secretion of type I interferons (IFN-I) and various pro-inflammatory cytokines [55, 56]. This process not only reverses immune exclusion within the microenvironment but also serves as a critical target for promoting DC maturation and the recruitment of tumor-specific CD8⁺ T cells, ultimately facilitating the conversion of “cold” tumors into “hot” ones [54, 57, 58]. Metabolically, the pronounced “Warburg effect” in CRC cells results in glucose deprivation and massive lactate accumulation within the microenvironment [59]. Lactate not only contributes to microenvironmental acidification, impairing T-cell cytotoxicity, but also stabilizes the immunosuppressive function of MDSCs via the Hypoxia-inducible factor-1α (HIF-1α) pathway. HIF-1α, which accumulates extensively under hypoxic conditions, not only triggers vascular abnormalities by driving the transcription of vascular endothelial growth factor (VEGF) but also further upregulates the expression of glycolytic enzymes [60, 61]. This aggravates metabolic competition, creating a vicious cycle of “hypoxia-metabolic inhibition-immune evasion” [62].

Physical blood vascular and lymphatic barriers

CRC, particularly MSS-CRC, is characterized by a typically dense physical barrier. The aberrant deposition of the extracellular matrix (ECM) represents a primary hallmark [63, 64]. CAFs secrete excessive amounts of collagen and hyaluronic acid, orchestrating the formation of a cross-linked and dense fibrotic matrix [65]. This not only leads to significantly elevated tumor interstitial fluid pressure (IFP), which impedes the deep penetration of drugs and nanoparticles, but also physically restricts the infiltration of T cells into the tumor core, creating an “immune desert” or“immune-excluded” landscape [66, 67]. Concurrently, the tumor vasculature exhibits structural and functional abnormalities. Driven by the overexpression of pro-angiogenic factors, tumor vessels are typically tortuous, dilated, and highly leaky, characterized by a distinct lack of pericyte coverage [68]. This dysfunctional vascular system results in insufficient blood perfusion, which exacerbates the hypoxic and acidic environment within the tumor, further compromising the survival and function of immune cells [69]. In addition to blood vessels, lymphatic vessels and lymphatic endothelial cells are active regulators of the tumor immune microenvironment. Tumor-associated lymphatics control interstitial fluid drainage, antigen transport, dendritic cell migration to tumor-draining lymph nodes, and immune-cell trafficking [70]. Lymphatic endothelial cells can guide CCR7-positive dendritic cells and T cells through CCL21-dependent chemotaxis, thereby influencing antigen presentation and T-cell priming. However, lymphatic remodeling may also facilitate tumor dissemination and immune tolerance, indicating that its immunological effects are highly context dependent [70, 71].

Experimental evidence demonstrates this dual role. Lymphatic remodeling and drainage influence the establishment of tumor-associated inflammation and the composition of the immune microenvironment. VEGF-C-driven lymphangiogenesis has been associated with increased T-cell infiltration and improved responses to immunotherapy, whereas impaired lymphatic function or blockade of lymphangiogenesis can promote tumor-supportive inflammation, alter macrophage composition, and accelerate tumor growth. Therefore, therapeutic strategies should aim to restore functional lymphatic transport and immune trafficking rather than simply suppressing lymphangiogenesis [72, 73].

The colorectal cancer immune microenvironment should be viewed as an interconnected cellular and structural network rather than a collection of independent therapeutic targets. Cancer-associated fibroblasts and extracellular matrix deposition compress blood and lymphatic vessels, increase interstitial pressure, and restrict nanoparticle penetration and immune-cell trafficking. In turn, vascular dysfunction, hypoxia, and lactate accumulation promote immunosuppressive immune-cell phenotypes. Lymphatic endothelial cells regulate antigen drainage, dendritic-cell migration, and T-cell trafficking, while activated immune cells can reciprocally remodel stromal and vascular compartments. Therefore, the therapeutic effects of nanoparticle-delivered Chinese medicine monomers depend on coordinated regulation of immune, stromal, vascular, lymphatic, and metabolic components.

Nanocarrier platforms for the delivery of TCM monomers

Organic nanocarrier platforms

Liposomes

Liposomes are the most established biomimetic phospholipid bilayer carriers used in CRC TCM delivery. They possess excellent biocompatibility and can simultaneously encapsulate both hydrophilic and hydrophobic drugs [74]. Additionally, liposomes enable the co-delivery of TCM monomers with chemotherapeutic agents and immune adjuvants, synergistically reversing multi-drug resistance (MDR) and reducing systemic toxicity. Their primary limitations include relatively low drug loading capacity, drug leakage during storage, and challenges in controlling batch stability for large-scale production [75].

Polymer nanoparticles

Due to the structural designability of synthetic and natural polymers, polymeric nanocarriers show immense potential in CRC-targeted delivery and smart drug release [76]. Limitations include the insufficient controllability of synthetic polymer degradation rates and issues with natural polymers, such as significant batch-to-batch variation and low transepithelial absorption efficiency following oral administration.

Polymer micelles

Formed by the self-assembly of amphiphilic block copolymers, polymeric micelles are preferred carriers for delivering poorly water-soluble TCM monomers in CRC treatment, significantly improving drug solubility and tumor targeting [74]. Their core defect is a tendency to disassemble under high dilution, leading to premature drug release and the need for optimized in vivo circulation stability.

Nanoemulsions

Nanoemulsions are thermodynamically unstable but kinetically stable colloidal systems composed of oil phases, aqueous phases, surfactants, and co-surfactants, with oil-in-water (O/W) types being the mainstream for TCM monomer delivery. Their core advantages include high encapsulation efficiency for lipophilic monomers and enhanced bioavailability via lymphatic absorption, which bypasses the hepatic first-pass effect. Additionally, they feature simple preparation processes and are easily adapted for industrial production [77].

Drug nanocrystals

Drug nanocrystals are nanoparticles consisting solely of drug crystals and a minimal amount of stabilizer, devoid of additional carrier matrices. With a drug-loading capacity approaching 100%, they resolve the critical “low loading” pain point of traditional nanocarriers [78]. Nanosizing significantly improves the dissolution rate and saturation solubility of poorly soluble TCM monomers, vastly increasing oral bioavailability. Furthermore, their preparation process is straightforward and suitable for large-scale production [79].

Inorganic nanocarriers

Mesoporous silica

Mesoporous silica nanoparticles (MSNs) feature controllable pore structures and extremely high drug-loading capacity. They are easily functionalized for the construction of various microenvironment-responsive delivery systems. Their limitations include slow in vivo degradation rates, potential toxicity from long-term accumulation, and difficulty in maintaining pore size uniformity during mass production [74].

Metal-based nanoparticles

Metal-based nanoparticles, primarily represented by gold nanoparticles (AuNPs) and magnetic iron oxide nanoparticles (IONPs), possess unique optical and magnetic properties, serving as vital carriers for integrated CRC theranostic (therapy + diagnostic) systems [80]. AuNPs exhibit excellent surface plasmon resonance (SPR) effects, enabling photoacoustic imaging and photothermal therapy (PTT), and their surfaces are easily modified with targeting ligands. IONPs possess superparamagnetism and can significantly activate anti-tumor immunity. Their limitations involve toxicity risks from long-term in vivo accumulation, insufficient surface modification stability, and a tendency toward aggregation [81].

Biomimetic nanocarriers

Albumin nanocarriers

Albumin nanocarriers utilize human serum albumin (HSA) as the core matrix [82]. They offer superior biocompatibility and can achieve tumor enrichment through the the enhanced permeability and retention (EPR) effect and receptor-mediated active targeting. Several formulations have already been approved for clinical use, providing a clear pathway for translational medicine [74, 83].

Cell membrane-coated nanocarriers

These carriers are constructed by coating a nano-core with natural cell membranes, combining the drug-loading capacity of nanoparticles with the natural biological traits of the membranes. This enables immune evasion and precise homologous targeting. Macrophage and erythrocyte membrane-coated systems can achieve inflammation-targeted delivery and ultra-long in vivo circulation, respectively, effectively enhancing the therapeutic efficacy of TCM monomers in CRC. Their limitations include complex membrane extraction and purification processes, difficulties in scale-up, and challenges in maintaining batch stability and protein activity [84].

Exosomal nanocarriers

Exosomes are natural nano-sized vesicles secreted by cells, offering excellent biocompatibility, transmembrane transport capabilities, and immune evasion traits, making them ideal for the oral delivery of TCM monomers. Exosomes derived from CRC cells or dendritic cells can achieve homologous targeting and enhanced antigen presentation, respectively, effectively activating anti-tumor immune responses. Limitations include complex purification and drug-loading processes, relatively low loading capacity, and incomplete quality control systems for mass production [85].

Carrier-free nanodrugs

Carrier-free nanodrugs require no additional matrix; they are formed solely through non-covalent self-assembly, such as π-π stacking and hydrophobic interactions, between TCM monomer molecules [86]. This approach fundamentally avoids the potential toxicity and immunogenicity of carrier materials while providing high drug loading and simplified preparation processes [87].

Moreover, nanocarriers can improve the pharmacokinetic properties of Chinese medicine monomers by enhancing solubility, reducing premature metabolism, prolonging circulation, and increasing tumor accumulation [33, 88]. Their therapeutic efficacy also depends on release kinetics, as premature release may increase systemic exposure, whereas excessively slow release may limit intratumoral drug availability. Stimuli-responsive systems can promote monomer release in response to tumor acidity, intracellular glutathione, reactive oxygen species, or tumor-associated enzymes [89]. However, the heterogeneity of these triggers may lead to variable drug release among tumors. Future studies should therefore report serum stability, burst release, release profiles, intratumoral drug concentrations, and tumor-to-normal tissue exposure ratios.

Intrinsic immunomodulatory effects of nanocarriers

Nanocarriers can actively modulate the tumor immune microenvironment rather than serving merely as passive delivery vehicles [90]. Liposomes and polymeric nanoparticles can enhance antigen uptake and presentation by dendritic cells and influence macrophage polarization through their particle size and surface properties [91]. Metal-based nanoparticles can generate reactive oxygen species and promote M1-like macrophage polarization, while manganese-containing systems may further activate the cGAS-STING signaling pathway and induce type I interferon production [92]. Biomimetic carriers, including cell membrane-coated nanoparticles and exosomes, can improve tumor accumulation and participate in immune communication [93].

However, carrier-induced inflammatory responses, complement activation, and off-target immunotoxicity should also be considered. These immunomodulatory effects are double-edged and are highly dependent on the composition, size, surface charge, dose, and degradation behavior of the nanomaterials. Under favorable conditions, they may enhance antitumor immunity; however, poorly designed nanocarriers may induce unintended inflammation, complement activation, or even immunotoxicity such as cytokine storms. A critical comparison of the drug-loading capacity, in vivo stability, potential toxicity, manufacturing feasibility, and clinical readiness of the major nanocarrier platforms is provided in Table 1.

Table 1.

Critical comparison of nanocarrier platforms for delivering Chinese medicine monomers

Nanocarrier platform	Relative drug loading	In vivo stability	Major toxicity concerns	Scale up and quality control	Relative clinical readiness
Liposomes	Moderate	Moderate to high but drug leakage may occur	Complement activation and lipid related infusion reactions	Manufacturing is relatively mature but requires strict control of size encapsulation free drug and leakage	High as a delivery platform
Polymeric nanoparticles	Moderate to high	Generally high	Polymer degradation products and residual solvents	Scalable but polymer molecular weight degradation and residual solvent require control	Moderate to high
Polymeric micelles	Moderate	Moderate with possible dilution induced dissociation	Premature release and surfactant related toxicity	Relatively scalable but critical micelle concentration and storage stability require monitoring	Moderate
Nanoemulsions	High for lipophilic monomers	Moderate	Surfactant irritation and physical instability	Comparatively simple production but droplet size phase separation and microbial stability require control	Moderate
Drug nanocrystals	Very high	Moderate	Drug precipitation and local concentration related toxicity	Simple composition and favorable scalability but crystal form size distribution and aggregation require control	Moderate to high
Mesoporous silica and metal organic frameworks	High	Moderate	Slow degradation residual inorganic components and tissue accumulation	Pore size metal content surface chemistry and batch uniformity are difficult to standardize	Low
Metal based nanoparticles	Low to moderate	High	Persistent accumulation oxidative stress and metal ion toxicity	Requires strict control of aggregation surface coating and residual metal	Low
Albumin nanoparticles	Moderate	High	Protein related immunogenicity and source variability	Established manufacturing principles but protein integrity and drug binding must be controlled	High as a platform
Cell membrane coated nanoparticles	Moderate	High	Source dependent immunogenicity pathogen contamination and unintended membrane signals	Difficult scale up because of membrane isolation purification protein preservation and batch variability	Low
Exosomes	Low to moderate	High	Source dependent biological activity and unintended cargo	Major challenges include cell source purification potency assays loading efficiency and storage	Low
Carrier free nanodrugs	Very high	Low to moderate	Aggregation precipitation and burst release	Simplified composition and potentially easier scale up but self assembly reproducibility and colloidal stability remain challenges	Low to moderate

Triple strategies for remodeling the immune microenvironment via nano-traditional Chinese medicine (nano-TCM)

“Igniting” anti-tumor immunity: nano-TCM monomers inducing ICD and pathway activation

In recent years, the use of nanoparticles to deliver active Chinese medicine monomers for the specific “ignition” of anti-tumor immune responses has emerged as a frontier strategy for remodeling the immune microenvironment. The core mechanisms of this approach primarily focus on inducing ICD, triggering pyroptosis, and activating the cGAS-STING signaling pathway (Fig. 2).

Fig. 2.

Ignition of antitumor immunity by Nano-TCM. Tumor-responsive nanocarriers induce ICD, pyroptosis, and cGAS-STING activation, thereby promoting dendritic-cell maturation, CD8-positive T-cell activation, and tumor-cell killing

Induction of ICD to promote antigen exposure

ICD drives tumor cells to release a suite of DAMPs during the cell death process—including calreticulin (CRT) surface exposure, ATP secretion, and HMGB1 release. These signals potently promote the maturation and antigen cross-presentation of DCs, ultimately activating tumor-specific CD8⁺ T cells. While the ability of free Chinese medicine monomers to induce ICD is often limited by poor bioavailability, nanodelivery systems significantly amplify this effect [94, 95]. Research indicates that smart nanosystems loaded with single natural products can achieve targeted release and highly efficient ICD induction. For instance, Li et al. (2025) developed pH-sensitive polymeric nanoparticles for the targeted delivery of resveratrol, effectively overcoming microenvironmental barriers and significantly triggering ICD in CRC cells [24]. Similarly, Mianowska et al. (2023) demonstrated that liposomal berberine could induce a robust ICD response while effectively killing colon cancer cells [96]. In addition, the Camptothesome developed by Wang et al. (2022) potently induce ICD, greatly enhancing the immune system’s own killing ability and paving the way for subsequent ICB therapy [97]. More importantly, nanotechnology provides an ideal platform for the co-delivery of Chinese medicine monomers with other agents to synergistically induce ICD. Sun et al. (2022) developed a cyclodextrin-based nanoformulation for the co-delivery of ginsenoside Rg3 and quercetin. At the molecular level, Rg3 induced immunogenic cell death, as indicated by calreticulin translocation, ATP secretion, and HMGB1 release, while quercetin enhanced intracellular reactive oxygen species generation. These damage-associated molecular patterns promoted dendritic cell maturation and subsequent CD8⁺ T-cell activation, thereby enhancing the response to immune checkpoint blockade [9]. Furthermore, paclitaxel (PTX) is frequently used as a chemo-immunomodulator in combination with Chinese medicine monomers. For example, Wu et al. (2025) reported polymeric nanoparticles co-loaded with PTX and alantolactone, while Zhang et al. (2019) designed a micellar system containing quercetin and alantolactone. Both systems amplified the ICD effect through multiple pathways, successfully converting immunologically “cold” tumors into “hot” ones [98, 99]. In addition, in the field of self-assembled nanomedicines inspired by the concept of TCM formulas, Mao et al. (2022) ingeniously utilized ursolic acid and lentinan for self-assembly, which not only successfully induced ICD but also simultaneously modulated the immunosuppressive microenvironment, achieving a perfect integration of “strengthening vital qi” to consolidate the body’s foundation with targeted intervention of the microenvironment [37].

Triggering pyroptosis and activating the cGAS-STING pathway

Nano-TCM monomers further ‘ignite’ immunity through non-apoptotic mechanisms; by inducing pyroptosis and activating cGAS-STING signaling, these formulations transcend the limitations of standard ICD to stimulate a robust inflammatory response. Pyroptosis, characterized by the formation of plasma membrane pores and the release of massive pro-inflammatory cytokines, can rapidly awaken a dormant tumor immune microenvironment. Cheng et al. (2024) developed a hyaluronic acid-modified calcium-based nanoinducer that responded to the acidic tumor environment by releasing Ca²⁺, curcumin, and H₂O₂. Mitochondrial Ca²⁺ overload and oxidative stress subsequently activated the caspase-3/GSDME axis, inducing pyroptosis and immunogenic cell death. The released inflammatory signals, together with M1-like macrophage polarization, promoted dendritic cell maturation and CD8⁺ T-cell-dependent antitumor immunity [100]. Simultaneously, the activation of the cGAS-STING pathway plays a pivotal role in promoting IFN-I secretion and subsequent T-cell recruitment. Nanocarriers, through their unique intracellular delivery advantages, assist TCM monomers in targeting this pathway more precisely. Eldurini et al. (2026) utilized a liposome-chondroitin sulfate/chitosan hybrid system to deliver curcumin, Xiao et al. (2024) designed curcumin-loaded hydroxyapatite (HAP) nanoparticles, and Cao et al. (2022) developed ROS-responsive camptothecin nanoparticles, all of which were confirmed to efficiently activate the cGAS-STING pathway [22, 101, 102]. Furthermore, the nanomedicine studies by Sun et al. (2020) on paclitaxel and Dana et al. (2022) demonstrated that paclitaxel/gemcitabine nanoparticles and resveratrol-loaded liposomes enhanced antitumor activity by promoting T-cell responses and disrupting tumor–fibroblast interactions, respectively [18, 103].

Broad-spectrum immunomodulation and apoptosis synergy

In addition to specifically inducing ICD and activating core signaling pathways, many nano-formulated Chinese medicine monomers exhibit powerful “General Immunomodulation” functions at a macroscopic level. Firstly, regarding the use of oral nanodelivery systems to improve the local intestinal immune microenvironment, Xia et al. (2025) developed berberine liposomes containing prebiotic inulin derivatives, which demonstrated exceptional local immunomodulatory capabilities [27]. Similarly, an earlier study by Kanwar et al. (2012) utilizing alginate-chitosan-encapsulated bovine lactoferrin for paclitaxel delivery confirmed that oral administration can trigger potent, broad-spectrum immune protection in colon cancer models [104]. Secondly, for the classic drug paclitaxel, multiple studies have confirmed that nano-formulation significantly downregulates systemic immunosuppression. Xiong et al. (2017) reported that mannose-modified liposomes improved the overall immune effect during paclitaxel treatment for colon cancer [105]. Furthermore, Parayath et al. (2016), using styrene-maleic acid-encapsulated paclitaxel micelles, and Hu et al. (2021), through the development of polymeric nanoparticles, achieved the synergistic restoration of systemic immune homeostasis and tumor cell apoptosis while overcoming MDR [106, 107]. Additionally, nano-formulations of natural polyphenols such as quercetin and resveratrol play an irreplaceable role in optimizing the overall cytokine profile of the TME. Regarding quercetin, the chitosan nanoparticles developed by Rashedi et al. (2019) and the self-assembled micelles by Xu et al. (2015) both significantly enhanced broad-spectrum anti-colon cancer activity [108, 109]. For resveratrol, Fu et al. (2025) detailed synergistic immune strategies using liposomal and hydrogel formulations, while Serini et al. (2018) co-loaded Omega-3 polyunsaturated fatty acids and resveratrol into solid lipid nanoparticles (SLNs), further amplifying anti-tumor immune activity [26, 110]. In terms of protective mechanisms for combination therapy, early research by Schwingel et al. (2014) compared resveratrol, rutin, quercetin, and a quercetin nanoemulsion for their effects on oxaliplatin-induced hepatotoxicity and neurotoxicity in mice [111]. This multi-pathway, pan-immune regulatory action complements targeted ICD and STING pathway activation, collectively constructing a comprehensive defense line to convert “cold” tumors into “hot” ones. Despite encouraging results, direct comparisons among these immune ignition strategies remain difficult because the available studies use different monomers, nanocarriers, doses, tumor models, and definitions of immunogenic cell death. Increased calreticulin exposure or HMGB1 release does not necessarily indicate durable systemic antitumor immunity. Future studies should therefore integrate release kinetics and intratumoral exposure with standardized measurements of dendritic cell activation, T cell responses, immune memory, and treatment related toxicity.

“Reprogramming” the innate immune soil: targeting TAMs and reshaping antigen presentation networks

Innate immune cells in the CRC microenvironment, particularly TAMs and DCs, are often “domesticated” by the tumor into accomplices that promote growth and immune escape. Nanodelivery technology empowers TCM monomers to precisely target and reverse these immunosuppressive phenotypes. By reshaping the antigen-presentation network, this approach fundamentally improves the “soil” of the TME, highly aligning with the TCM principle of “eliminating stasis and toxins” to restore microenvironmental homeostasis (Fig. 3).

Fig. 3.

Reprogramming of the immune cell network by Nano-TCM. Nanoformulated monomers promote M1-like macrophage polarization and dendritic-cell maturation, reduce MDSC and Treg-mediated immunosuppression, and enhance CD8⁺ T-cell infiltration and cytotoxicity

Reversing TAM polarization

TAMs typically exhibit a pro-tumor M2 phenotype in the CRC microenvironment, serving as a core element of the immunosuppressive barrier. Numerous studies show that nano-formulated TCM monomers can efficiently induce the reprogramming of TAMs toward the anti-tumor M1 phenotype. Delivery systems based on MOFs and their derivatives show great potential here. Babaei et al. (2025) developed a curcumin-loaded biodegradable Bio-MOF that penetrates the TME to achieve TAM phenotypic reversal [36]. Similarly, Ye et al. (2024) reported biomimetic ZIF/MOF platforms for ginsenoside delivery. These monocyte/macrophage-mediated systems achieved deep penetration and precise regulation of polarization, yielding strong synergistic effects with PD-1 inhibitors [10]. Additionally, hybrid exosomes and polymeric technologies offer new paths. Xie et al. (2024) utilized hybrid exosomes for paclitaxel delivery, leveraging membrane homing to reshape macrophages [112]. Long et al. (2023) designed shikonin polymeric nanoparticles that regulated TAMs while reversing epithelial-mesenchymal transition (EMT) during CRC liver metastasis [19].

Promoting DC maturation and in situ nano-vaccination

As professional antigen-presenting cells (APCs), the maturation state of DCs directly determines the efficiency of T-cell activation. By combining Chinese medicine monomers with biomimetic nanotechnology, these systems can function as in situ “nanovaccines” to potently activate DCs. Taking gambogic acid (GA) as an example, Huang et al. (2023) innovatively encapsulated GA nanoparticles within colorectal cancer cell membranes to construct a biomimetic nanovaccine [113]. This strategy perfectly integrates the TAA repertoire with the immuno-adjuvant effect of GA. It not only significantly promotes DC maturation and antigen cross-presentation but also enhances targeting to draining lymph nodes (dLNs) via the homing effect. This approach opens a new frontier for the application of Chinese medicine monomers in the field of cancer vaccines.

Receptor-mediated precise intervention

To more efficiently deliver traditional Chinese medicine monomers to innate immune cells or specific tumor lesion sites, researchers have introduced various targeting modifications on the surface of nanocarriers. Zheng et al. (2025) reported that baicalein targets adenosyl homocysteinase (AHCY) to inhibit H3K4me3-mediated cancer stemness in MSI CRC, [39]. The targeted multifunctional nanosystem designed by Xie et al. (2025) for ginsenoside Rg3, with its ability to target glucose transporter 1 (Glut1), enhanced liposome uptake in HCT116 cells and improved the accumulation of chemotherapeutic drugs within tumors [114]. Both approaches achieved efficient enrichment of drugs in the TME. Additionally, the curcumin peptide vesicles developed by Zhao et al. (2020), guided by CD133-targeting peptides, specifically targeted tumor cells and achieved a transition from mucosal adhesion to penetration [115]. Regarding the targeted delivery of paclitaxel, Ansari et al. (2025) and Sang et al. (2024) further confirmed that receptor-mediated targeting strategies can maximize its immunomodulatory efficacy [17, 116]. Furthermore, for specific mutant-type intestinal cancers, Yalikong et al. (2021) utilized HER2-targeted nanodelivery systems loaded with triptolide, which significantly inhibited the proliferation of HER2-positive and BRAF-mutant colon cancers [117]. These advancements further expand the boundaries of precision therapy for nano-formulated Chinese medicine monomers. Although targeted and biomimetic systems can improve immune cell or tumor uptake, their efficacy depends on heterogeneous receptor expression and the biological characteristics of the source membrane. Moreover, macrophage polarization and dendritic cell maturation may be influenced by both the loaded monomer and the carrier itself. Future studies should distinguish carrier mediated effects from drug mediated effects and evaluate whether increased targeting complexity provides sufficient therapeutic benefit to justify the associated manufacturing and quality control burden.

“Normalizing” physical and metabolic barriers: reversing hypoxia, regulating metabolism, and remodeling stroma

CRC evades immunosurveillance not only through intercellular signaling but also by constructing a dense desmoplastic stroma and an extreme metabolic environment, forming robust physical and chemical barriers. Nano-formulated Chinese medicine monomers have demonstrated unique pharmacological advantages in “normalizing” these microenvironmental barriers (Fig. 4).

Fig. 4.

Normalization of physical and metabolic barriers by Nano-TCM. Nanoformulations reduce lactate accumulation and hypoxia, inhibit cancer-associated fibroblasts and extracellular matrix deposition, and improve nanoparticle penetration and effector T-cell infiltration

Regulating immunometabolism

Due to the Warburg effect, tumor cells produce large amounts of lactate, which not only directly inhibits the proliferation and cytolytic activity of T cells but also promotes the infiltration of immunosuppressive cells. Nano-formulations of Chinese medicine monomers can target and intervene in tumor metabolic pathways, reducing the production of metabolic “toxins” like lactate at the source. Studies by Long et al. (2023) have discussed in depth the critical role of shikonin polymeric nanoparticles in regulating lactate-related immunometabolism [19]. These nano-formulations effectively lower local lactate concentrations and restore the metabolic fitness of T cells. Additionally, regarding metabolic intervention with curcumin, Gong et al. (2021) and Javadi et al. (2018) utilized micelles to deliver curcumin, improving the overall metabolic environment by upregulating key metabolic enzymes such as pyruvate dehydrogenase kinase 4 (PDK4), thereby yielding a significant synergistic effect with anti-PD-1 therapy [15, 118].

Alleviating tumor hypoxia

Hypoxia is one of the most typical microenvironmental features of solid tumors; it upregulates HIF-1α, which further recruits Tregs and MDSCs, creating a vicious cycle of immunosuppression. Utilizing the catalytic properties of nanomaterials for in situ oxygen generation is an effective strategy to alleviate microenvironmental hypoxia. Liu et al. (2022) designed an innovative curcumin nano-formulation encapsulated in a manganese dioxide (MnO₂) shell, while Meng et al. (2018) developed MnO₂-modified albumin-bound paclitaxel nanoparticles [119, 120]. Both utilize the property of MnO₂ to catalyze oxygen production by reacting with endogenous hydrogen peroxide (H₂O₂) in the acidic tumor microenvironment. This strategy not only directly mitigates hypoxia but also synergistically enhances sensitivity to radiotherapy, chemotherapy, and immunotherapy. Simultaneously, the gambogic acid hydrogel system by Lei et al. (2025) and the research by Dewi et al. (2024, 2022) using nanodiamonds to deliver quercetin focus on the precise regulation of both metabolic and hypoxic pathways, providing substantial empirical evidence for reversing hypoxia-induced immunosuppression [25, 121].

Remodeling desmoplastic stroma

The abundance of CAFs and excessively deposited ECM in CRC construct a dense physical barrier that hinders the deep penetration of nanodrugs and the infiltration of effector T cells. Targeting and inhibiting CAFs is key to breaking this physical barrier. Research by Fourniols et al. (2020) achieved potent inhibition of CRC-associated fibroblasts using paclitaxel-loaded lipid nanocapsules [122]. Barrier normalization should also be approached cautiously. Excessive extracellular matrix depletion or vascular disruption may increase tumor invasion or impair drug retention, whereas inorganic catalytic materials may introduce additional oxidative stress and long term accumulation. The timing and extent of stromal, vascular, and metabolic remodeling should therefore be optimized using biomarkers of perfusion, hypoxia, interstitial pressure, and immune cell infiltration.

Clinical translation and remaining challenges

Although nanoparticle-delivered Chinese medicine monomers have shown promising therapeutic efficacy in preclinical colorectal cancer models, their clinical translation remains limited [33, 123]. To date, no nanoparticle formulation of Chinese medicine monomers has been approved for the clinical treatment of colorectal cancer, and most available evidence is still based on in vitro and animal studies. In contrast, the clinical success of liposomal formulations and albumin-based nanoparticles demonstrates the feasibility of nanotechnology as a drug delivery platform [124, 125].

The limited clinical translation of nanoformulated Chinese medicine monomers is mainly attributed to challenges in scalable manufacturing, batch-to-batch consistency, quality control, and long-term biosafety evaluation [126]. Preclinical studies suggest that nanoformulations may improve systemic tolerability compared with free or conventional formulations, as reflected by reduced body-weight loss, fewer abnormalities in hematological and serum biochemical parameters, less histopathological damage to major organs, and, in some cases, increased maximum tolerated doses. However, clinical data on the incidence and severity of adverse events remain scarce, and the current evidence therefore supports improved preclinical tolerability rather than a clinically confirmed reduction in systemic toxicity [88]. Selected Chinese medicine monomers may also help alleviate immune-related adverse events associated with immune checkpoint inhibitors, particularly immune-related colitis, through their anti-inflammatory and mucosal-protective effects. However, excessive immune suppression may compromise antitumor efficacy. Therefore, their dose, timing, and tissue-specific delivery require careful evaluation. Current evidence remains mainly preclinical, and further clinical studies are needed [127]. Moreover, off-target accumulation in the liver, spleen, and other healthy tissues may still cause systemic toxicity, while the combined immunomodulatory effects of monomers and nanocarriers may induce excessive inflammation or immunotoxicity. Conventional animal models also cannot fully reproduce the complexity of the human colorectal cancer immune microenvironment. Future studies should therefore prioritize standardized manufacturing, comprehensive pharmacokinetic and biosafety assessment, and clinically relevant models, including patient-derived organoids and humanized animal models, to facilitate clinical translation.

Conclusion

Nano-delivery technologies represent a promising strategy for improving the therapeutic potential of Chinese medicine monomers in colorectal cancer. This review summarized three mechanisms: “igniting” immunity via ICD and pathway activation; “reprogramming” the innate soil via TAMs and DCs; and “normalizing” barriers by alleviating hypoxia and remodeling stroma (Table 2). Representative studies combining nanoparticle-delivered Chinese medicine monomers with immunotherapies are summarized in Table 3. Notably, the available evidence remains entirely preclinical, and no clinical study specifically evaluating these combination strategies in colorectal cancer has yet been identified. Systematic evaluation of long-term toxicity and off-target accumulation of complex nanomaterials is urgent [12, 128]. Although substantial preclinical progress has been achieved, further efforts are required to address manufacturing scalability, quality control, long-term biosafety, and clinical validation before these nanoformulations can be translated into routine clinical practice. Transitioning from “smart” lab-scale NPs to compliant with good manufacturing practice (GMP)-compliant mass production is a major hurdle. Conventional animal models often fail to reflect human CRC diversity [129]. Future research should employ patient-derived organoids and identify precise biomarkers [130]. Moving forward, a “simple yet smart” design philosophy, combined with interdisciplinary efforts in materials science, pharmaceutics, and immunology, will likely push nano-TCM formulations past the translational bottleneck to benefit patients with advanced CRC [131].

Table 2.

Active ingredients of TCM and their mechanisms in CRC immunotherapy

TCM Source	Active Ingredient	Nanocarrier Types	Key Immunological Mechanisms	Refs
Huzhang (Polygoni Cuspidati Rhizoma et Radix)	Resveratrol	Polymer nanoparticles	Induces ICD	[24]
Huanglian (Coptidis Rhizoma)	Berberine	Liposomes	Induces ICD	[96]
Xishu (Camptothecae Acuminatae Fructus)	Camptothecin	Carrier-Free Nanodrugs	Induces ICD	[97]
Renshen + Huaimi (Ginseng Radix et Rhizoma + Sophorae Flos Immaturus)	Ginsenoside Rg3 + Quercetin	Polymer nanoparticles	Induces ICD	[9]
Hongdoushan + Tumuxiang (Taxus Chinensis + Inulae Radix)	Paclitaxel + Alantolactone	Polymer nanoparticles	Induces ICD	[98]
Huaimi + Tumuxiang (Sophorae Flos Immaturus + Inulae Radix)	Quercetin + Alantolactone	Polymer micelles	Induces ICD	[99]
Xiakucao + Xianggu (Prunellae Spica + Lentinula Edodes)	Ursolic acid + Lentinan	Carrier-Free Nanodrugs (Self-assembled)	Induces ICD	[37]
Jianghuang (Curcumae Longae Rhizoma)	Curcumin	Metal-Based Nanoparticles	Triggers pyroptosis	[100]
Jianghuang (Curcumae Longae Rhizoma)	Curcumin	Liposomes	Activates cGAS-STING pathway	[101]
Jianghuang (Curcumae Longae Rhizoma)	Curcumin	Metal-Based Nanoparticles	Activates cGAS-STING pathway	[102]
Xishu (Camptothecae Acuminatae Fructus)	Camptothecin	Polymer nanoparticles	Activates cGAS-STING pathway	[22]
Hongdoushan (Taxus Chinensis)	Paclitaxel	Organic Nanocarrier Platforms	General immunomodulation	[18]
Huzhang (Polygoni Cuspidati Rhizoma et Radix)	Resveratrol	Organic Nanocarrier Platforms	Remodels desmoplastic stroma	[103]
Huanglian + Juju (Coptidis Rhizoma + Cichorii Radix)	Berberine + Inulin derivatives	Liposomes	General immunomodulation	[27]
Hongdoushan + Bovine Lactoferrin (Taxus Chinensis + Bovine Lactoferrin)	Paclitaxel + Bovine lactoferrin	Polymer nanoparticles	General immunomodulation	[104]
Hongdoushan (Taxus Chinensis)	Paclitaxel	Liposomes	General immunomodulation	[105]
Hongdoushan (Taxus Chinensis)	Paclitaxel	Polymer micelles	General immunomodulation	[106]
Hongdoushan (Taxus Chinensis)	Paclitaxel	Polymer nanoparticles	General immunomodulation	[107]
Huaimi (Sophorae Flos Immaturus)	Quercetin	Polymer nanoparticles	General immunomodulation	[108]
Huaimi (Sophorae Flos Immaturus)	Quercetin	Polymer micelles	General immunomodulation	[109]
Huzhang (Polygoni Cuspidati Rhizoma et Radix)	Resveratrol	Liposomes	General immunomodulation	[26]
Huzhang + Omega-3 PUFAs* (Polygoni Cuspidati Rhizoma et Radix + Omega-3 PUFAs)	Resveratrol + Omega-3 PUFAs	Organic Nanocarrier Platforms (Solid lipid nanoparticles)	General immunomodulation	[110]
Huzhang + Huaimi (Polygoni Cuspidati Rhizoma et Radix + Sophorae Flos Immaturus)	Resveratrol + Quercetin	Nanoemulsions	General immunomodulation	[111]
Jianghuang (Curcumae Longae Rhizoma)	Curcumin	Metal-Based Nanoparticles	Reverses TAM polarization	[36]
Renshen (Ginseng Radix et Rhizoma)	Ginsenoside	Biomimetic Nanocarriers	Reverses TAM polarization	[10]
Hongdoushan (Taxus Chinensis)	Paclitaxel	Exosomal Nanocarriers	Reverses TAM polarization	[112]
Zicao (Arnebiae Radix)	Shikonin	Polymer nanoparticles	Reverses TAM polarization immunometabolism	[19]
Tenghuang (Garciniae Resina)	Gambogic acid	Cell Membrane-Coated Nanocarriers	Promotes DC maturation	[113]
Renshen (Ginseng Radix et Rhizoma)	Ginsenoside Rg3	Liposomes	Receptor-mediated targeted intervention	[114]
Jianghuang (Curcumae Longae Rhizoma)	Curcumin	Organic Nanocarrier Platforms	Receptor-mediated targeted intervention	[115]
Hongdoushan (Taxus Chinensis)	Paclitaxel	Organic Nanocarrier Platforms	Receptor-mediated targeted intervention	[17]
Hongdoushan (Taxus Chinensis)	Paclitaxel	Biomimetic Nanocarriers	Receptor-mediated targeted intervention	[116]
Leigongteng (Tripterygii Wilfordii Radix)	Triptolide	Organic Nanocarrier Platforms	Receptor-mediated targeted intervention	[98]
Jianghuang (Curcumae Longae Rhizoma)	Curcumin	Polymer micelles	Regulates immunometabolism	[15]
Jianghuang (Curcumae Longae Rhizoma)	Curcumin	Polymer micelles	Regulates immunometabolism	[118]
Jianghuang (Curcumae Longae Rhizoma)	Curcumin	Metal-Based Nanoparticles	Alleviates tumor hypoxia	[120]
Hongdoushan (Taxus Chinensis)	Paclitaxel	Albumin Nanocarriers	Alleviates tumor hypoxia	[119]
Tenghuang (Garciniae Resina)	Gambogic acid	Polymer nanoparticles	Regulates immunometabolism and Alleviates hypoxia	[25]
Huaimi (Sophorae Flos Immaturus)	Quercetin	Inorganic Nanocarriers	Regulates immunometabolism and Alleviates hypoxia	[121]
Hongdoushan (Taxus Chinensis)	Paclitaxel	Liposomes	Remodels desmoplastic stroma	[122]

Table 3.

Representative preclinical studies of nanotechnology delivered Chinese medicine monomers combined with immunotherapies for colorectal cancer

Chinese medicine monomer	Nanocarrier	Main immunological mechanism	Major findings	Evidence level	Ref
Ginsenoside Rg3 and quercetin	Folate targeted PEGylated cyclodextrin nanoparticles	Rg3 induced ICD through CRT exposure ATP secretion and HMGB1 release while quercetin enhanced ROS generation thereby promoting DC maturation and CD8 positive T cell activation	Enhanced the response to PD L1 blockade and remodeled the immunosuppressive TME	Preclinical	[9]
Curcumin	Reduction sensitive disulfide crosslinked polymeric micelles	GSH responsive curcumin release improved systemic exposure and tumor delivery and enhanced antitumor immune responses	Curcumin micelles showed synergistic tumor inhibition with anti PD 1 therapy	Preclinical	[118]
Camptothecin	Sphingomyelin derived camptothecin nanovesicles termed Camptothesome	Induced ICD promoted DC activation and increased granzyme B and perforin mediated cytotoxic T cell responses	Potentiated checkpoint blockade suppressed primary and distant tumors and induced immune memory	Preclinical	[97]
Ginsenoside Rg1 and atractylenolide I	Apoptotic body membrane coated ZIF nanoparticles	Rg1 promoted DC maturation whereas atractylenolide I increased tumor MHC I expression thereby enhancing CTL infiltration and tumor recognition	Sensitized MSS CRC to PD 1 blockade and markedly improved tumor inhibition	Preclinical	[10]

Author contributions

MZ: Writing - original draft, Investigation, Writing - review & editing, Visualization, Table preparation. LH: Writing - original draft, Writing - review & editing, Visualization. LQ, CC, and DL: Writing - original draft, Writing - review & editing, Visualization. TL: Writing - original draft, Writing - review & editing. XJ: Writing - review & editing, Supervision, Funding acquisition, Conceptualization.

Funding

This work was supported by the Research Project on Improving the Level of Clinical Evidence for Traditional Chinese Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences (No. XYZX020107) and the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences (No. CI2021A01911).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

Not applicable. This article is a review study and does not contain any studies with human participants or animals performed by any of the authors.

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Not applicable. This article does not contain any individual person’s data in any form.

Competing interests

The authors declare no competing interests.