Self-assembled nanodrug delivery systems for anti-cancer drugs from traditional Chinese medicine

Abstract

Traditional Chinese medicine (TCM) is a combination of raw herbs and herbal extracts with a plethora of documented beneficial bioactivities, which has unique advantages in anti-tumor therapy, and many of its major bioactive molecules have been identified in recent years due to advances in chemical separation and structural analysis. However, the major chemical classes of plant-derived bioactive compounds frequently possess chemical properties, including poor water solubility, stability, and bioavailability, that limit their therapeutic application. Alternatively, natural small molecules (NSMs) containing these components possess modifiable groups, multiple action sites, hydrophobic side chains, and a rigid skeleton with self-assembly properties that can be exploited to construct self-assembled nanoparticles with therapeutic effects superior to their individual constituents. For instance, the construction of a self-assembled nanodrug delivery system can effectively overcome the strong hydrophobicity and poor in vivo stability of NSMs, thereby greatly improving their bioavailability and enhancing their anti-tumor efficacy. This review summarizes the self-assembly methods, mechanisms, and applications of a variety of NSMs, including terpenoids, flavonoids, alkaloids, polyphenols, and saponins, providing a theoretical basis for the subsequent research on NSMs and the development of SANDDS.

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1. Introduction

Malignant tumors are a major cause of premature death, and mortality rates are rising in many regions around the world despite the advances in treatment.^1,2 According to the latest data from the International Agency for Research on Cancer (IARC), there were 19.29 million new cancer cases and 9.96 million cancer-related deaths globally in 2020, including 4.57 million new cases and 3 million deaths in China. In fact, China accounts for the greatest proportion of new cases (23.7%) and deaths (30%) worldwide.³ The pathogenesis of malignancy is complex, and both prevention and control are difficult due to the multitude of risk factors. Further, many tumor types still lack effective treatment strategies, especially at advanced stages. At present, the main treatment strategy is surgical resection of the tumor supplemented by chemotherapy and (or) radiotherapy because surgical resection alone frequently does not completely eradicate all tumor tissue. However, traditional chemotherapy drugs are also variably toxic against non-cancerous tissues, resulting in intolerable side effects.⁴

In this case, traditional Chinese medicine (TCM) is a promising alternative treatment for many cancers given that these plant-based formulations demonstrate multiple synergistic or additive modes of action, fewer and less severe side effects, and reduced propensity for inducing drug resistance than synthetic anti-cancer agents.⁵ Moreover, recent advances in chemical separation and structural analysis have led to the identification of many major anti-tumor agents in TCM.⁶ Another potential significant advantage of the natural small molecules (NSMs) present in Chinese medicinal herbs is their higher biological safety when used as either primary drugs or carriers for other anti-cancer drugs due to their lower inherent cytotoxicity and tissue accumulation. However, many potent anti-tumor agents from TCM have physical and chemical properties that limit their medicinal use, such as poor water solubility, stability, and bioavailability. Conversely, some of these agents, including various terpenoids, flavonoids, alkaloids, polyphenols, and saponins, have chemical moieties that facilitate self-assembly into multicomponent nanoparticles (NPs) with enhanced bioavailability.⁷

Nanotechnology has numerous applications in medicine, especially for the targeted delivery of anti-cancer drugs. Nanodrug delivery systems (NDDSs) can effectively improve the physical and chemical properties of parent drugs, thereby overcoming physiological barriers to tumor accumulation, reducing off-target toxicity, prolonging the bioavailability, and ultimately enhancing the treatment efficacy.^8–10 Nanodrug delivery systems can be constructed without an inactive dedicated carrier, which are termed carrier-free drug-delivery systems (CFDDSs).¹¹ Nonetheless, most nanodrugs still require ionic materials, surfactants, or amphiphilic structures to maintain their stability and function. In recent years, CFDDSs have been developed with high drug-loading capacity, low off-target toxicity, and minimal immunogenicity for cancer treatment.^12–14 Further, self-assembly technology holds enormous potential for the development of new drugs.^15,16 In self-assembled nanodrug delivery systems (SANDDSs), NSMs form nanocarrier complexes spontaneously through non-covalent bonds (including van der Waals forces, hydrogen bonds, π–π stacking, halogen bonds, hydrophobic interactions, cation–π bonds, ionic bonds, CH–π bonds and solvation) under equilibrium conditions and can be combined with photosensitizers or other drug molecules to form nano-sized multifunctional drug complexes targeting tumor tissues.¹⁷

The chemical structures of TCM components are often complex, including side chains with self-assembly characteristics, and many previous studies have used these features to improve the clinical applicability of the core bioactive NSMs for the development of SANDDSs.^18,19 Additional structural components can also be added, although these modifications must be simple to preserve the inherent biological safety and pharmacological activities of the parent compound.^20,21 The construction of carrier-free SANDDSs based on the self-assembly characteristics of NSMs in particular can greatly improve the drug curative effects by conferring greater tissue targeting and water solubility than traditional synthetic anti-cancer drugs.²² Recently, Xie and colleagues reviewed the self-assembly mechanisms of TCM-derived NSMs and the clinical potential of these NSMs for the treatment of cancers and neurological diseases. They concluded that further research on the self-assembly of NSMs will accelerate the development of these compounds for clinical treatment.²³

The construction of SANDDSs can effectively mitigate the clinical limitations caused by the strong hydrophobicity and poor in vivo stability of many TCM-derived NSMs, thereby enhancing their bioavailability and anti-tumor efficacy.^17,24 The self-assembly processes may involve the active components of TCM preparations, other clinical anti-cancer compounds, metal chelators, prodrugs, tracers, inhibitors, and (or) photosensitizers, but in all cases the aim is to overcome the suboptimal physical and chemical properties of NSMs. In addition to improved clinical anti-cancer activity, the self-assembly of TCM compounds has great research value, given that it may reveal specific interactions between components and provide clues to even more effective drug combinations. Moreover, Hou and coworkers proposed that the spontaneous formation of multicomponent complexes through self-assembly holds the greatest promise for improved therapeutic efficacy because free drugs seldom possess the bioactivity of the complete TCM preparation.²⁵ Specifically, the interactions among ingredients within the same complex has a great impact on the therapeutic efficacy. For instance, heat reflux and water decoction inadvertently create appropriate conditions for the formation of natural assemblies, and these assemblies both eliminate the toxicity of component drugs and improve the water solubility of the bioactive components.²⁶ Herein, we describe the SANDDSs of TCM-derived terpenoids, flavonoids, alkaloids, polyphenols, and saponins (as shown in Fig. 1). By summarizing the self-assembly applications of existing NSMs and further exploring the possible mechanisms of self-assembly (as shown in Table 1), this review aims to provide a theoretical basis for the future research and development of SANDDSs.

Table 1 Common self-assembled systems and mechanism of the main active components in traditional Chinese medicine

Category	Natural product	Plant source	Self-assembly mechanism	Self-assembled systems	Advantages	Ref.
Terpenoids	Oleanolic acid	Ligustrum lucidum	Electrostatic, π–π stacking, hydrophobic interactions	OA/GA NPs	Good stability and sustained release	36
			π–π stacking and hydrophobic interaction	OC	Improved solubility, efficacy and safety of the OA	40
	Betulinic acid		π–π stacking, hydrophobic interactions	BA-S-S/Ce6 NPs	Improved multiple combination antitumor therapies	29
	Betulinic acid	White birch	Hydrogen bonding, hydrophobic interactions	BA/PTX NPs	Improved cancer therapeutics efficiency	44
			π–π stacking	BA-Ce6 NPs	Enhanced synergistic anticancer efficacy	45
	Dihydroartemisinin	Artemisia annua	Hydrogen bonding, hydrophobic interactions	DHA NPs	Good stability, high drug loading efficiency, and responsive release.	59
	Dihydroartemisinin	Artemisia annua	Hydrophobic interactions	CD NPs	Prolonged blood circulation time	61
Flavonoids	Quercetin	Panax notoginseng	Hydrophilic-hydrophobic interactions	HA-Que micelles	Improved the drug targeting	69
			hydrophobic interactions	TQ-Que NPs	Accumulate better in mitochondria	72
	Myricetin	Myrica rubra	Hydrophobic interactions	Casein nanocapsules	Good biodegradability	76
			Coordination interactions	MZG nanoparticles	Good bioavailability and biocompatibility,	78
	Baicalin	Scutellaria baicalensis Georgi	Electrostatic interactions, hydrogen bonding	DOX/SA-SS-BAI NPs	Improving the tumor targeting	83
			Dynamic covalent bonds	BAI hydrogels	Improved antibacterial activities	85
Alkaloids	Berberine	Coptis chinensis	Hydrogen bonds and π–π stacking	BBR and CA co-assembly	Good therapeutic efficacy against	92
			Electrostatic and hydrophobic interactions	BBR-BAI NPs	Good biocompatibility	93
			Electrostatic and π–π stacking interactions	The self-assembly of BBR and AA	Blocked the toxicity of AA	100
	Camptothecin	Camptotheca acuminata	Hydrophilic-hydrophobic interactions	Camptothecin-Dipeptide Nanotubes	Improved the loading and the stability	107
			Hydrophilic-hydrophobic and π–π stacking interactions	Self-assembly of CPT and carbamoyl mannose conjugates	Reduced acute renal injury	108
			Hydrophobic interactions	SN38/Ce6 NPs	Enhanced cell absorption and tumor accumulation	114
			Hydrophobic interaction and π–π stacking	Taxol-CPP nanospheres	Exhibit efficient cytotoxicity	121
	Paclitaxel	Taxus brevifolia	Hydrophobic interactions	The self-assembly of PTX-S-S-VE prodrug	High drug loading efficiency	123
			π–π stacking	SePTX NPs	Selectivity towards cancer cells	124
			Hydrophobic force and halogen bonds	F8-SS-PTX NPs	Exhibited good antitumor effect	125
Polyphenols	Curcumin	Curcuma longa	Coordination interactions	Cur-Ca@DMSNs-FA	Enhanced anti-tumor effect	138
			Coordination interactions	ICG@cur-GdNPs	Enhanced the MR and fluorescence imaging and anticancer treatments	140
	Tannic acids	Chinese gallnut	Coordination interactions	DOX-Al^3+-TA capsule	Reduced cytotoxicity and strengthened targeting	151
			Coordination interactions	siRNA/EGCG/protamine nanocomposites	Overcome the drug resistance	159
	Other Polyphenols			Sm^3+-EGCG nanocomposite	Induced apoptosis in cancer cell through mitochondrial dysfunction	163
Saponins	Ginsenosides	Ginseng-derived compounds	Hydrogen bonding and hydrophobic interactions	GSN	Enhanced anti-tumor efficacy and drug targeting, and reduces systemic toxicity	189
	Ginsenosides	Ginseng-derived compounds	Hydrogen bonding and both hydrophobic and electrostatic interactions	INS@GS NPs	Improved the stability and good hypoglycemic efficiency	191
	Ginsenoside Rg3	Ginseng-derived compounds	Hydrogen bond interaction	Rg3-PTX-LPs	Enhanced glioma targeting and intratumoral diffusion capability	204
	Glycyrrhetinic acid	Licorice	Hydrophilic-hydrophobic interactions	CpG-EXO/TGM	Increased the solubility of drug	212

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Fig. 1 Schematic diagram of natural small molecules (NSMs) (terpenoids, flavonoids, alkaloids, polyphenols, and saponins) commonly used to construct self-assembled nanodrug delivery systems.

2. NSMs-based SANDDS

2.1 Terpenoids

All derivatives of isoprene (terpene) with the general molecular formula C₅H₈(n) are called terpenoids. According to the number of isoprene units, these compounds are classified as monoterpenes, sesquiterpenes, diterpenes, and triterpenes. Terpenoids are widely distributed in gymnosperms, and most are aromatic liquids. Many natural terpenoid small molecules (NTSMs) have anti-cancer activity and important applications in drug research and development, such as betulinic acid (BA) extracted from white birch and oleanolic acid (OA) extracted from Ligustrum lucidum. In addition to anti-tumor activity, terpenoids possess strong self-assembly capacity,²⁷ which is attributed to their multi-hydroxyl and multi-carboxyl structures. Moreover, terpenoids can be used to assemble SANDDSs containing photosensitizers and other anti-cancer drugs (including other NSMs from TCMs) through hydrogen bonding, hydrophobic interaction, and π–π stacking. Terpenoids can complete self-assembly in aqueous solution through hydrophobic and hydrogen bond interactions due to their unique hydrophobic skeleton and the hydrogen bond donors and acceptors of NTSMs.²⁸ The UV-vis spectra of some assembly systems also show that π–π stacking is a critical driving force in the molecular self-assembly of terpenoids.

Further, NTSMs can also self-assemble with other NSMs to form natural drug carriers with better biosafety and compatibility as well as broader functionality than conventional anti-cancer agents due to their unique biological activities such as hepatoprotection and suppression of drug resistance.²⁹ Through self-assembly technology, NTSMs can also improve the bioavailability of commonly used clinical anti-tumor drugs such as paclitaxel (PTX) and cisplatin. In addition, NTSMs can be efficiently self-assembled with photosensitizers, possibly due to the π–π stacking of the isoprene structure, to produce nanostructures that can combine chemotherapy and photodynamic therapy (PDT) for an enhanced anti-tumor effect.³⁰

2.1.1. Oleanolic acids. Oleanolic acids (OAs) are pentacyclic triterpene compounds with anti-cancer, hepatoprotective, hypoglycemic, and anti-viral activities, which are widely used to induce the self-assembly of small molecules in TCMs.³¹ Drug carriers constructed using OAs have also demonstrated better biosafety than free OAs.^32,33

Bag³⁵et al. confirmed the potential of self-assembly for drug development with statistics, especially using OA and the triterpene BA. Liu et al.³⁴ showed that the chemical structure of terpenoids gives them strong self-assembly capacity, completing self-assembly with photosensitizers or other anticancer drugs through the hydrogen bonding interaction of hydroxyl and π–π stacking and hydrophobic interactions of the skeleton, between which π–π stacking is a key driving force for the self-assembly of terpenoid molecules. Also, the differences in the spatial orientation of the basic backbone and the carboxyl, such as nano- or micro-sized fibers, tubes, spheres, and flower- and grass-like fibers facilitate their self-assembly. Furthermore, OA can be co-assembled with glycyrrhetinic acid (GA) to construct drug carriers. Wang and colleagues developed a nanocarrier with multiple biological activities via self-assembly of OA and GA, and reported a drug loading efficiency of 15% for the traditional anti-cancer drug PTX. Moreover, OA, GA, and PTX showed synergistic anti-tumor activities. In addition, the drugs loaded on OA/GA NPs also demonstrated good stability and sustained release characteristics, while the NSMs conferred hepatoprotective and anti-inflammatory activities.³⁶

Tumors are a heterogeneous disease with uncontrolled evolution over time, and in many cases, a single treatment strategy cannot completely inhibit tumor growth.³⁷ Furthermore, tumors are prone to relapse, drug resistance and spreading, and drug therapy of tumors has problems such as difficult real-time monitoring of the drug processes in vivo, multi-drug resistance of tumors, and insufficient carrier targeting. However, traditional cancer treatment methods have limitations such as many adverse reactions, poor specificity, and easy to cause drug resistance. Accordingly, the combination of traditional therapy with photothermal therapy (PTT), chemodynamic therapy (CDT), sonodynamic therapy (SDT) and immunotherapy has been proven to be an effective way to treat cancer.³⁸ For instance, sono-photodynamic therapy (SPDT) is a combination of PDT and sonodynamic therapy (SDT) with better anti-cancer efficacy than its individual modalities.³⁹ Similarly, the combination of chemotherapeutic drugs and PDT may possess superior efficacy than each alone. Chloroe6 (Ce6) is a chlorophyll derivative with photodynamic and sonodynamic effects, which is often used as an initiator in cancer treatment. Zheng and colleagues reported that a carrier-free nanosensitizer drug formed using OA and Ce6 through self-assembly produced effective combined chemotherapy and SPDT (Fig. 2). After intravenous injection of OC, OC reaches the tumor site through the EPR effect, and then enters cancer cells. Under stimulation from light and ultrasound, OC can exert synergistic chemotherapy and SPDT by producing ROS, decreasing MMP, and inducing cell apoptosis. The self-assembly of OA with Ce6, possibly via electrostatic, π–π stacking, or hydrophobic interactions, was not only relatively simple, but the product demonstrated good monodispersity and photostability in aqueous solution. Compared to free drugs, drugs combined with OC via self-assembly have demonstrated greatly improved solubility, efficacy, potency, and safety. More importantly, OC shows potent toxicity against tumor cells, and thus OC-mediated synergistic therapy has great potential to improve cancer therapeutics.⁴⁰

Fig. 2 Schematic diagram of the self-assembly of oleanolic acid and chlorin e6 nanoparticles (OC) and their application for anti-tumor therapy. Reprinted with permission from ref. 40. Copyright (2021), Elsevier.

2.1.2. Betulinic acid. Betulinic acid (BA) is an abundant monohydroxytriterpene acid with demonstrated anti-cancer, anti-tumor, anti-viral, and anti-hyperglycemic activities^41,42 as well as excellent self-assembly properties. It was also the first triterpene small molecule used for self-assembly without derivatization.⁴³

The bioavailability, side-effect profile, and therapeutic efficacy of the first-line anti-cancer agent PTX can be improved by self-assembly with BA. Wang and coworkers formed supramolecular co-assembled nanoparticles from BA and PTX through hydrogen and hydrophobic interactions and found that these BA/PTX NPs retained both the characteristics of the nanoparticles and the activities of the constituent NSMs. Further, BA/PTX NPs showed good anti-tumor efficacy in vivo and vitro due to the improved biocompatibility and safety conferred by using NSMs as carriers, as well as the synergy between BA and PTX due to their distinct modes of action. Infrared and ultraviolet spectra also indicated that hydrogen bonding and hydrophobic interactions are the main driving force for the co-assembly of BA and PTX. This study by Wang and colleagues provides a template for future research on NSM carrier drugs and a rationale for the choice of pentacyclic triterpenoids as NSM carriers.⁴⁴

Cheng and colleagues screened eleven small molecules that can self-assemble with Ce6 for combined chemotherapy/PDT and found that BA-based nano-co-assemblies (BA-Ce6 NPs) combined with PDT achieved 93.6% tumor cell eradication. In addition, NTSMs can be constructed through π–π stacking without any other external force for self-assembly. Compared to the free drug and Ce6, BA-Ce6 NPs also demonstrated better stability and dispersion, longer blood circulation time, and greater tumor accumulation, highlighting the advantages of self-assembled NSMs as a new drug-delivery platform.⁴⁵

The efficacy of PDT is dependent on the generation of reactive oxygen species (ROS); however, the ROS produced by PDT in the tumor microenvironment (TME) may be consumed by glutathione (GSH), which is overproduced in tumor cells.⁴⁶ Thus, Cheng and coworkers designed and synthesized a natural pentacyclic triterpene BA modified with a disulfide bond (BA–S–S), and then constructed a new carrier-free delivery system with BA–S–S and Ce6 for synergistic anti-cancer enhancement and improved PDT biosafety. Also, given that the disulfide bond enables the drug to respond to GSH, Ce6 produces sufficient ROS for efficient PDT, and both in vitro and in vivo treatment studies demonstrated that this modified NP preparation significantly enhanced the synergistic anti-tumor effect, while still maintaining good biodegradability and biocompatibility.²⁹

2.1.3 Ursolic acid. Ursolic acid (UA) is another pentacyclic triterpenoid compound with a variety of biological activities, including anti-cancer, anti-inflammatory, antibacterial, and anti-diabetes activities.^47,48 However, UA is poorly water soluble, is rapidly cleared from plasma, and has weak oral availability, which limit its application.⁴⁹ Alternatively, UA demonstrates efficient self-assembly, and thus has also been used to produce SANDDSs for cancer treatment.⁵⁰

Cheng and colleagues designed a multifunctional SANDDS for combined chemotherapy and PTD by assembling Ce6 with disulfide-modified UA, yielding UASS-Ce6 NPs, and reported good self-assembly using simple preparation methods and a better therapeutic effect on tumor cells than individual Ce6 and UA treatment. Moreover, the introduction of disulfide bonds ensured robust ROS-induced cytotoxicity even in the presence of GSH. In addition, depending on the characteristics of the NSM used, these dual-function nanodrugs can show better biocompatibility, safety, and biodegradability than raw NSMs given that the whole assembly structure acts as a therapeutic drug.⁵¹

UA possesses unique drug characteristics compared to other terpenoids, which can prevent drug resistance by tumor cells, and thus improve the therapeutic effect. For instance, the combination of UA and cisplatin can effectively overcome multiple cisplatin inactivation pathways in ovarian cancer cells. Wang and colleagues constructed a reductive reactive platinum(IV) (Pt(IV))/UA/polyethylene glycol (PEG) dual prodrug (Pt(IV)-UA PEG) complex to treat cisplatin-resistant ovarian cancer and reported that the released UA and cisplatin had distinct anti-cancer mechanisms and that the synergistic effects overcame the detoxification and anti-apoptosis mechanisms of cancer cells. In addition, the Pt(IV)-UA NPs in A2780/DDP showed a prolonged blood circulation time, enhanced tumor accumulation, and significantly improved anti-tumor efficacy without detectable side effects in tumor-bearing mice.⁵²

UA itself could be formulated into nanosize or microsize carriers, and many SANDDSs based on UA have been constructed for drug delivery against various cancers.⁵³ However, the poor tumor targeting and low solubility of UA still affect its curative effect.⁵⁴ Some studies have shown that structural modification of drugs can alter their physical and chemical properties. The carboxyl and hydroxyl groups on the UA structure can be used for polymerization to form poly UA.⁵⁵ Then, poly UA can self-assembly into NPs via the nano-precipitation method. Ou et al. synthesized poly(ursolic acid) (PUA) utilizing the hydroxyl and carboxyl groups of UA via polycondensation, where PUA could self-assemble into nanoparticles (PUA-NPs).⁵⁰ PTX was selected as a model drug to generate PTX-loaded nanoparticles (PUA-NPs@PTX) against colorectal cancer. In vitro studies showed that PUA-NPs@PTX has strong cytotoxicity against colorectal cancer CT26 cells, while the in vivo results indicated that PUA-NPs@PTX can prolong the blood circulation time, enhance the tumor accumulation, and significantly improve antitumor efficacy in CT26 tumor-bearing mice (Fig. 3).

Fig. 3 Illustration of the major steps involved in PTX delivery by PUA-NPs@PTX to treat colorectal cancer. Reprinted with permission from ref. 50. Copyright (2020), Wiley.

2.1.4. Dihydroartemisinin. Dihydroartemisinin (DHA) is an artemisinin derivative isolated from the natural medicinal plant Artemisia annua, which has been extensively utilized as an antimalarial drug for decades. DHA also has good anti-cancer potential in treating various cancers.⁵⁶ However, its poor water solubility, rapid blood clearance and low bioavailability limit its clinical application.⁵⁷ Therefore, to improve the treatment efficiency of DHA, several DHA prodrugs and self-assembly nano-drug delivery systems were constructed to improve its anticancer-therapy activities.⁵⁸

In recent research, a carrier-free DHA nanodrug (DHA NPs) was prepared by the self-assembly of DHA molecules via hydrogen bonding and hydrophobic interactions (Fig. 4).⁵⁹ The DHA NPs possessed a monodispersed spherical morphology with a mean diameter of 93 nm. The DHA NPs also exhibited good stability, high drug loading efficiency, and responsive release. The in vitro and in vivo experiments showed that the DHA NPs exhibited significantly higher therapeutic efficacy than the free DHA. Furthermore, they revealed the potential molecular mechanism of the DHA NPs by RNA-seq and Western blotting analysis. Some hydrophobic prodrugs could self-assemble into prodrug nanoparticles, which have shown great potential in drug delivery systems with high drug-loading efficiency and favorable therapeutic effect.⁶⁰ Luo and colleagues designed albumin-binding and light-triggered core–shell dimeric prodrug nanoparticles (Ce6&DHA-S-DHA@CMN NPs, CDC NPs).⁶¹ Firstly, the ROS-sensitive single thioether bridge DHA dimer (DHA-S-DHA) was prepared. Then, the dimeric prodrug DHA-S-DHA self-assembled into nanoparticles (CD NPs) via a simple nanoprecipitation method. Finally, CD NPs were encapsulated with Chlorin e6 (Ce6) and stabilized by albumin-capturing maleimide- and hypoxia-sensitive 2-nitroimidazole-modified carboxymethyl chitosan (CMCTS-MAL&NI, CMN), and CDC NPs were obtained. The results showed that the novel CDC NPs with long blood circulation and light-triggered drug release were successfully established for chemo-photodynamic combination therapy against hypoxia-induced metastasis of lung cancer (Fig. 5).

Fig. 4 Schematic diagram of the preparation of self-assembled DHA NPs and their application in cancer treatment. Reprinted with permission from ref. 59. Copyright (2023), The Royal Society of Chemistry.

Fig. 5 Schematic illustration of DHA-S-DHA self-assembling into CDC nanoparticles (A) and its applications for chemo-photodynamic combination therapy (B). Reproduced from ref. 61 with permission from (Elsevier), Copyright (2021).

2.2 Flavonoids

Flavonoids are abundant and diverse secondary metabolites of plants.⁶² Originally, ‘flavonoid’ was the general name given to the class of compounds derived from 2-phenylchromone, but now refers to a series of compounds formed by connecting two benzene rings through three carbon atoms (general structure C6–C3–C6). Similar to most NSMs, flavonoid small molecules have numerous biological activities, including antibacterial, anti-viral, hypoglycemic, anti-tumor, anti-inflammatory, and antioxidant effects, but their use in the pharmaceutical industry and clinical applications is limited due to their low water solubility.^63–65 In drug research and development, self-assembly is mainly used to improve the physical and chemical properties of flavonoids. Amphiphilic compounds are obtained by connecting hydrophilic groups, and self-assembly is completed by hydrophobic interactions to obtain nanoparticles with improved water solubility and bioavailability. Through self-assembly, flavonoids can be connected to phospholipids, lecithins, hydrophilic macromolecular proteins, or borates to form water-soluble vesicles or micellar drug molecules in which the hydrophobic components act as a container for central hydrophobic drugs, and the hydrophilic components contact water in biological fluids to form a shell.

2.2.1 Quercetin. Quercetin (Que) is a polyphenol flavonoid abundant in plants such as Panax notoginseng, Ginkgo biloba, mulberry, and several other TCMs with a wide range of documented pharmacological effects, including scavenging oxygen free radicals, chelating transition metals, and inhibiting inflammation.⁶⁶ However, due to its poor hydrophilicity, low water solubility, instability in the gastrointestinal tract, extensive first pass metabolic effects, and low oral availability among other shortcomings, its clinical application is greatly limited.⁶⁷ Consequently, many Que-based NDDS have been constructed.^65,68

To further enhance the anti-tumor efficacy of Que, Pang and colleagues constructed a coupling polymer to improve its water solubility.⁶⁹ The hydroxyl group of Que was connected to HA premodified by adipic acid diamine (ADH) through succinate ester, yielding an amphiphilic polymer (adipic acid-modified hyaluronic acid). Subsequently, hyaluronic acid–Que micelles were synthesized through self-assembly. In addition to the hydrophobic effect of the amphiphilic polymer, the driving force for self-assembly of the coupling compound, i.e., the skeleton in HA, can form a hydrophilic shell by hydrogen bonding with the surrounding water molecules. The cytotoxicity of HA–Que micelles was 4-fold greater against MCF-7 cells (a CD44-overexpressing cell line) compared to free Que. In addition, HA–Que micelles demonstrated a 20-fold greater in vivo half-life and good inhibitory effects on tumor growth in H22 tumor-bearing mice. Hemolytic toxicity and intravenous stimulation tests further indicated that the HA–Que micelles were safe and effective NDDSs for targeted anti-tumor therapy. Although HA can increase cell uptake and targeting and has good biocompatibility and biodegradability, the modification with ADH can further improve drug targeting by forming ester bonds with Que to achieve pH-controlled release.

Chen and coworkers developed a Que-loaded micellar anti-cancer drug-delivery system based on lecithin, which demonstrated good therapeutic effects against breast cancer cells⁷⁰ due to the improved physical and chemical properties of Que and concomitantly higher bioavailability. The addition of lecithin to the micellar system also increased the volume of the hydrophobic core, thereby providing more space for the dissolution of hydrophobic drugs and a higher drug loading capacity.

Mitochondrial signaling and metabolic output are critical for the evolution and progression of cancer, and thus targeted mitochondrial NDDSs may be particularly effective treatments.⁷¹ Xing and colleagues constructed a mitochondrial-targeted SANDDS based on amphiphilic TPP–Que conjugates.⁷² Triphenylphosphine (TPP) is the most commonly used mitochondrial ligand and has shown high efficacy for delivering drugs to mitochondria. To improve the stability of the coupling compound, PEG was introduced in the catechol structure of phenylboronic acid (PBA) and Que in the form of coordination bonds. The special catechol structure of Que makes it possible to polyglycolate with PBA–PEG through coordination bonds. A TPP–Que coupling compound was successfully synthesized through a nucleophilic substitution reaction. After PEGylation, the obtained TQ–PEG NPs exhibited better stability, thus prolonging the circulation time and enhancing the tumor-targeting effect. In addition, the coordination bond made the polymer pH responsive, thereby enhancing PEG removal for increased activity on tumor mitochondria. Compared to free Que, TQ–PEG NPs accumulated in mitochondria in vivo and in vitro and showed significant anti-cancer effects. More importantly, the TPP–Que conjugates self-assembled into nanoparticles, indicating that self-assembly is mainly driven by hydrophobic interactions rather than hydrogen bonds or ion interactions.

To improve the bioavailability of Que, Liu and colleagues constructed Que-Quinoa protein (QP)-Lotus root amylopectin (LRA) nanoparticles (Que-QP-LRA).⁷³ It was shown that Que can self-assemble with QP to greatly improve its solubility. However, the bioavailability of Que was not greatly improved due to the influence of active enzymes and gastric acid in the stomach. Therefore, Liu and colleagues coated Que-QP with LRA to obtain nanoparticles with a more regular spherical shape. In vitro simulated digestion experiments showed that Que-QP-LRA NPs improved the stability of Que in the stomach and absorption across the gastrointestinal tract. Molecular interaction analysis also showed that hydrogen bonding and hydrophobic interactions are the main driving forces for the formation of Que-QP-LRA nanoparticles.

2.2.2 Myricetin. Myricetin (Myr) is a natural flavonoid extracted from the fruit of Myrica rubra, which is widely studied because of its high antioxidant, anti-inflammatory, antibacterial, and anti-cancer efficacies.⁷⁴ Recently, Gupta reviewed its many applications, including the treatment of cancer, diabetes, epilepsy, heart disease, osteoporosis, and Alzheimer's disease.⁷⁵ However, the high hydrophobicity and low bioavailability of Myr greatly limit its clinical application.

Macromolecular proteins have better biocompatibility, biodegradability, and biosafety, and thus Guo and colleagues combined Myr with macromolecular proteins to improve its physical and chemical properties, while retaining its efficacy.⁷⁶ The dietary protein casein also has good biodegradability and biocompatibility when taken orally, and in addition is an amphiphilic protein with good self-assembly characteristics. The hydrophobic sites of these proteins can be self-assembled with Myr through hydrophobic interactions, and the preparation process is simple. Guo and coworkers used the self-assembly method to prepare casein Myr nanocapsules and observed that the absorption efficiency was four-times that of standard Myr samples, thus greatly improving its utilization efficiency.

Oxidative stress is caused by an imbalance between the cellular generation of prooxidants (from oxidative phosphorylation in mitochondria and various other metabolic reactions) and cellular antioxidant capacity, which can cause irreversible damage to cell components and even lead to cancer and other diseases.⁷⁷ Moreover, oxidative stress is a critical pathomechanism in many chronic diseases. Therefore, the development of antioxidant agents is an important strategy to slow the development of chronic diseases and to maintain redox balance for optimal cell function and general health. Myricetin has strong antioxidant capacity given that it not only can chelate intracellular transition metal ions to prevent Fenton-like reactions, but can also upregulate antioxidant enzymes and related signaling pathways to increase total cellular antioxidant capacity. Glutathione is the primary free antioxidant peptide in cells and is used as an electron donor by several antioxidant enzymes. To obtain an effective and practical antioxidant, Ma and colleagues⁷⁸ co-assembled Myr, Zn²⁺, and GSH into Myr–Zn²⁺–GSH (MZG) nanoparticles, which demonstrated high water solubility, good bioavailability and biocompatibility, and a stable antioxidant effect. The main driving force for the formation of MZG was coordination interactions, which are the strongest non-covalent interactions, thus ensuring better stability under physiological conditions and stable antioxidant performance without affecting the clearance of ROS by Myr and GSH.

2.2.3 Baicalin. Baicalin (BAI) is a bioactive component isolated from Scutellaria baicalensis Georgi with documented sedative, hypotensive, antibacterial, diuretic, anti-inflammatory, anti-metamorphosis, antioxidant, immunosuppressive, and pro-apoptotic effects on liver cancer cells.⁷⁹ However, due to its poor water solubility, low permeability, and extremely low oral bioavailability, its clinical applications are still limited. It is known that BAI and berberine can self-assemble in aqueous solution to form nanoparticles that not only greatly increase the solubility of BAI but also enhance therapeutic efficacy against some diseases.⁸⁰ Jia and colleagues also constructed a new insulin delivery mode with BAI and aluminum chloride.⁸¹ Wang et al. reported that BAI and sanguinarine can directly self-assemble through non-covalent bonds such as electrostatic attraction, π–π stacking, and hydrogen bonding.⁸²

Although BAI has good curative effects on tumors, its poor water solubility and permeability also limit clinical applications. Therefore, it is usually combined with macromolecules to form amphiphilic compounds as drug carriers for improved therapeutic effects. Zhang and coworkers⁸³ used cystamine as the connecting arm to graft BAI with sodium alginate (SA), forming a SA-BAI NDDS through hydrophobic or electrostatic action, which was used as a carrier for the anti-cancer agent doxorubicin (DOX) to obtain DOX/SA-SS-BAI NPs. SA greatly enhanced the water solubility of this drug, while cysteamine, as a connecting arm, could be specifically induced by GSH at the tumor site to release DOX and BAI, thereby improving the tumor targeting and reducing exposure of healthy tissue. Indeed, the inhibitory effect of DOX/SA-SS-BAI NPs on cancer cells was higher than that of free BAI or DOX, while the drug loading and encapsulation efficiency of the carrier were satisfactory.

O-carboxymethyl chitosan (OCMC) has a large number of active amino groups that are amenable to chemical modification, while lactic acid (LA) can be specifically recognized by ASGP-R receptors on the membrane of liver parenchyma cells and quickly absorbed by endocytosis. Therefore, Shao and colleagues connected BAI and LA to OCMC through an amidation reaction and loaded DOX to produce a new anti-cancer treatment⁸⁴ that releases BAI and DOX in the TME through active targeting and enhanced permeability and retention (EPR) for a synergistic effect on the tumor but reduced toxic side effects. To improve the physical and chemical properties of BAI for greater bioavailability, Wang and colleagues prepared a dynamic covalent hydrogel by combining BAI directly with borate through the boric acid α-hydroxycarboxylic acid group and catechol structure.⁸⁵ The dynamic boric acid bond is reversible and covalent, which endowed the hydrogel with excellent stability, plasticity, and self-healing. Further, BAI could also contribute to therapeutic effects after intravenous injection due to its endogenous antibacterial activity, including good therapeutic efficacy against Staphylococcus aureus infection.

The self-assembly strategy can improve the bioavailability and the clinical efficacy of the NSMs. Coptidis Rhizoma (CR) and Scutellariae Radix (SR) are classical TCM combinations in clinic, which are used as the herb pair CR-SR. Huang et al. selected the CR-SR main component berberine-baicalin (BBR-BAI) as examples to reveal the differences and mechanisms of self-assemblies originating from the co-decoction and physical mixture, respectively.⁸⁶ This study showed that the physical mixture morphology of both the herb pair (CR-SR) and the phytochemicals ((BBR-BAI)) was nanofibers (NFs), while their co-decoction morphology was nanospheres (NPs). This result indicates that temperature can affect the arrangement of the assembly (Fig. 6).

Fig. 6 Illustration displaying the differences between berberine–baicalin self-assemblies formed by physical mixing and decocting. Reprinted with permission from ref. 86. Copyright (2022), BMC.

2.3. Alkaloids

Alkaloids are natural alkaline organic compounds, most of which have complex ring structures, containing nitrogen atoms. They are important active ingredients in many TCM with numerous bioactivities but are poorly soluble in water.⁸⁷ However, alkaloids such as berberine, PTX, and camptothecin (CPT) are widely studied for potential clinical use and SANDDS development.²⁸ Berberine (BBR) from Coptis chinensis is often self-assembled with NSMs of other TCMs to improve its inherently disadvantageous physical and chemical properties, while enhancing its anti-tumor and antibacterial efficacy. Camptothecin derived from Camptotheca acuminata is often conjugated to polypeptide molecules by self-assembly through π–π stacking and hydrophobic interactions to improve bioavailability. Moreover, the ester bond and succinyl bond used for conjugation can be hydrolyzed at the tumor site to improve the drug targeting and release of the CTP precursor for enhanced tumor accumulation. In addition, due to their structural properties and metal chelation capacity, some alkaloids can be conjugated with photosensitizers to produce molecules for combined chemotherapy plus PDT. Alkaloids can also be self-assembled with NSMs and other substances to yield multifunctional drugs that retain their original bioactivity but with improved water solubility and bioavailability.

2.3.1. Berberine. Berberine (BBR) is a natural benzylisoquinoline and quaternary ammonium alkaloid isolated from Coptis chinensis. It has multiple pharmacological activities, including antibacterial, anti-cancer, hypolipidemic, anti-diabetes, and anti-diarrheal activities, but may have the greatest potential as an anti-cancer agent.^88,89 However, its clinical application is limited by its extremely low oral bioavailability (<1%). Several NDDSs have been developed by exploiting the aromatic rings and quaternary ammonium ions.^90,91 Historically, Coptis chinensis has been combined with other TCM preparations, suggesting that berberine has better clinical efficacy when combined with other bioactive components. Indeed, BBR demonstrates improved antibacterial efficacy when combined with cinnamic acid or BAI. Further, BBR can improve the properties of other bioactive ingredients. For example, the addition of BBR greatly reduces the toxicity of aristolochic acid, thus enhancing the promise of aristolochic acid (and Asarum) as a potential clinical agent. The cationic structure and nitrogen-containing rings of BBR facilitate simple self-assembly with other agents via hydrogen bonds and π–π stacking. The ring nitrogen atoms can form hydrogen bonds with carbonyl and other structures, and its cationic structure can generate electrostatic interactions that combine with π–π stacking and hydrophobic interaction to drive self-assembly.

Huang and colleagues⁹² reported a two-component self-assembly model for combining plant chemicals such as BBR and cinnamic acid (CA) into nanoparticles through intermolecular hydrogen bonding and π–π stacking. The success of this self-assembly was successfully verified through infrared spectroscopy, ultraviolet spectroscopy, field-emission scanning electron microscopy, and transmission electron microscopy (TEM). It is speculated that the initial self-assembly involves two molecules of BBR and two molecules of CA, which form a butterfly-like structure with CA as the body and BBR as the wings. The conjugation of two molecules depends on the formation of hydrogen bonds between the CA carbonyl group and BBR nitrogen atom, while their respective aromatic rings π–π stack to form spherical nanoparticles with stronger biofilm removal capacity than each compound individually. The authors further demonstrated that these NPs can spontaneously adhere to the bacterial surface, penetrate cells, and induce a polymerization attack on methicillin-resistant Staphylococcus aureus (MRSA). Through transcriptome analysis and quantitative polymerase chain reaction analysis, the multipathway bactericidal mechanism of NPs against MRSA was described. In addition, these NPs were found to be non-hemolytic in vivo and vitro, with low toxicity for the effective and safe treatment of MRSA infection.

Due to the clinical misuse of antibiotics, bacterial resistance is rising, creating an urgent need for novel antibiotic drugs with distinct mechanisms of action. The design of new drugs through self-assembly technology of natural molecules may be one solution, given that these compounds not only have high drug loading capacities and multiple bioactivities, but also good safety profiles. Li and colleagues developed new antibiotics by self-assembling BBR and BAI into nanoparticles.⁹³ BBR is a natural hydrophobic cation, which first combines via the electrostatic interaction between the –COO– of the flavonoid glycoside and the BBR N⁺ to form a one-dimensional complex unit. Then the hydrophobic flavonoid nuclei of BAI and BBR approach each other to form a basic unit that can further form NPs. Hydrophobic interactions further drive their self-assembly into three-dimensional nanostructures with hydrophilic glucuronic acid directed outward and the hydrophobic parent nucleus inward. With the extension of the hydrophilic glucuronic acid, the NPs showed stronger affinity for bacteria and greater efficacy for biofilm reduction. In vitro hemolysis tests, cytotoxicity tests, and in vivo toxicity evaluation of zebrafish demonstrated that the self-assembled products are highly biocompatible, which provides a foundation and direction for the production of other nano-antibacterial drugs.

BBR and BAI are the active components of the Huanglian Jiedu Decoction (consisting of rhubarb and Scutellaria baicalensis). A comprehensive analysis of the supernatant and natural sediment of the Huanglian Jiedu Decoction by Chen and coworkers⁹⁴ revealed a significantly higher BAI and BBR content in the sediment than in the aseptic precipitation of the supernatant, suggesting their self-assembled complexation in this TCM prescription. The formation of a BAI-BBR complex was studied by electrospray ionization (ESI)-mass spectrometry, nuclear magnetic resonance, ultraviolet visible (UV vis), Fourier transform infrared (FTIR), and fluorescence spectroscopy. Subsequently, the morphology and size distribution of the BAI-BBR self-assembled nanoparticles were characterized by SEM, TEM, and dynamic light scattering. This study provides strong evidence for self-assembled phytochemical compounds in natural sediments and provides a better understanding of Huanglian Jiedu Decoction activities.

The development of mitochondrial-targeting probes for the induction of metabolic dysfunction in tumor cells combined with tumor imaging is a promising strategy for cancer diagnosis and treatment,⁹⁵ where BBR has several advantageous characteristics for this application, including natural mitochondrial targeting, a cationic structure, and fluorescence properties from its unique aromatic rings suitable for imaging.⁹⁶ However, due to its π-conjugated structure, BBR shows low anti-cancer efficacy and low fluorescence quantum yield in practical applications. Thus, to improve both its anti-cancer efficacy and quantum yield, An and colleagues synthesized dehydroberberine (DH-BBR), a planar molecule with a complete π-conjugated four-ring structure⁹⁷ for longer fluorescence emission wavelengths and higher fluorescence quantum yield. Moreover, the planar structure could allow for better intermolecular interactions to promote self-assembly. In fact, DH-BBR was found to self-assemble into monodispersed organic nanoparticles (DTNPs) after integration with the lipophilic anion tetraphenylborate (TPB). After intravenous injection, DTNPs entered the tumor tissue more effectively, selectively accumulated in mitochondria, emitted stronger fluorescence, and caused greater mitochondrial dysfunction than BBR, thus inducing more effective tumor shrinkage.

Berberine can also be modified with TMC-derived NSMs to reduce the drug toxicity. Aristolochic acid (AA) is a nitrophenanthrene organic acid compound isolated from Aristolochia plants such as Aristolochia and Asarum.⁹⁸ It is reported to cause a series of health problems, such as acute kidney injury and liver cancer. Therefore, the use of medicinal plants containing AA is restricted or prohibited.⁹⁹ However, if the toxicity of AA can be neutralized by molecular modification, the application scope of AA-containing medicinal plants can be expanded. Wang and colleagues speculated that the self-assembly of BBR and AA could neutralize the toxicity of AA.¹⁰⁰ This assembly was initially driven by the electrostatic attraction between the carboxyl group of AA and the quaternary ammonium ion of BBR, and then by π–π stacking and hydrophobic interaction, yielding a linear, large-scale, and strong self-assembly. Due to the large assembly binding constant, a series of assembly driving forces and various π–π stacking sites are closely assembled. Notably, the assembly structure protects the carboxyl sites of AA from being metabolized into the toxic aristolochic lactam. Thus, this self-assembly strategy provides a chemical basis for detoxification. Indeed, systemic toxicological studies in zebrafish and mice showed that the supramolecular self-assembly of BBR and AA significantly reduced acute renal injury induced by AA.

2.3.2. Camptothecin. Camptothecin (CPT) is a natural small molecule alkaloid isolated from Camptotheca acuminata with strong anti-tumor activity.¹⁰¹ The lactone structure of CPT is considered to be the active site for tumor therapy given that it can inhibit DNA topoisomerase, and thus disrupt proliferation.¹⁰² However, some characteristics of CPT limit its clinical application, such as its low water solubility, fast blood clearance, poor tumor accumulation, and relatively poor stability in the physiological environment.^103,104 Alternatively, combining CPT with polypeptides through ester bonds, succinyl bonds, and self-assembly to form new nanodrugs has shown promise for improved efficacy. The water solubility of CPT can be improved by connecting hydrophilic amino acids or polypeptide molecules, and the ester bond and succinyl bond can hydrolyze and release CPT within the tumor tissue. Hydrophobic interactions and π–π stacking are the main driving forces of CPT polypeptide molecular self-assembly.

Camptothecin is difficult to dissolve but easy to form aggregates because of the strong π–π accumulation of its quinoline ring. Guo and colleagues¹⁰⁵ enhanced the water solubility of CPT by conjugation to hydrophilic arginine via ester bonds, which allowed CPT to be selectively released by hydrolysis. It was also found that this modified-CPT could self-assemble into helical nanofibers through π–π stacking and hydrophilic–hydrophobic interactions. The nanofiber could be effectively taken up by cells and were easily absorbed by the nuclei of tumor cells. Moreover, in vivo, nanofibers showed the best tumor inhibition effect, and this phenomenon was attributed to the assembled nanofibers better accumulating in the tumor and entering cells.

Sun and colleagues synthesized a CPT lysine A coupling compound through succinic acid conjugation¹⁰⁶ and found that its self-assembled into water-soluble uniform nanotubes suitable as drug carriers due to its high loading capacity (60.5%). The nanotube structure also provides a good hydrophobic environment for CPT, and indeed CPT in this formation showed good cell uptake and toxicity in vitro against several tumor cell lines.

Kim reported a self-assembly system of two CPT-coupled dipeptides, in which CPT molecules were linked to amino acids by succinyl bonds.¹⁰⁷ Fourier transform-IR showed that the main driving force for self-assembly was amphiphilic phase separation in aqueous solution. Subsequently, these CPT dipeptides were assembled into nanotubes with diameters in the range of 80–120 nm in PBS. The nanotube structure isolates the CPT segment in the hydrophobic nanotube wall, thereby protecting the drug from the opening of hydrolyzed lactones. Further, the succinyl bond permits the easy release of the active CPT via hydrolysis, and the rate of release is strongly dependent on its concentration. This dipeptide nanostructure can improve drug loading and CPT stability without excipients or macromolecular carriers.

Wang and colleagues developed a new method to conjugate CPT with carbamoyl mannose¹⁰⁸ and reported good self-assembly. In this design, CPT is meant to act as an anti-tumor agent and promote self-assembly, while carbamoyl mannose was chosen to enhance the selectivity for tumor cells. The carbamoyl mannose group points to water as a hydrophilic group, while the CPT group turns in the opposite direction as a hydrophobic tail to form nanotubes. Self-assembly is mainly mediated by hydrophobic–hydrophilic interactions and π–π interactions between the CPT skeletons. Through this assembly, the anti-cancer activity and water solubility of CPT greatly increased, and cancer cell apoptosis could be efficiently induced.

Anti-cancer regimens that include drugs with imaging functions are valuable given that they permit the monitoring of the biological distribution and circulation of therapeutic drugs as well as therapeutic responses in real time. Recent studies have shown that camptothecin can be self-assembled into a drug with imaging function. DOTA is a widely used metal chelating agent that can effectively chelate lanthanide metals, and thus used in a variety of imaging and radiotherapy applications. Su and colleagues directly conjugated CPT to DOTA, and then self-assembled the complex under physiological conditions to obtain the prodrug SPAD with glutathione responsiveness for improved tumor targeting.¹⁰⁹ The two hydrophobic CPT molecules provide strong π–π interaction to promote the directional growth of monomers, while DOTA increases the water solubility, promotes the self-assembly of the prodrugs into nanostructures, and can bind metal ions at the outer surface. SAPD was reported to have significant in vitro toxicity against a variety of cancer cell lines and effectively inhibit the growth of tumor globules.

The CPT analog 10,11-methylenedioxy-camptothecin (FL188) has even better anti-cancer effects and selective activity, but due to its low solubility and adverse side effects, it needs to be further optimized.¹¹⁰ ES-285 is an aliphatic amino alcohol with long saturated hydrophobic hydrocarbon side chains. It has good anti-proliferation activity against cancer cells, but also has low water solubility.¹¹¹ Zhang and colleagues¹¹² used FL188 and ES-285 to prepare two hydrophobic prodrugs (DHPs, FL-1 and FL-2), which were self-assembled into nanoparticles to improve their water solubility. The obtained DHPs and FL118 promoted the formation of nanoparticles (FL-2NPs) through π–π stacking of the conjugated aromatic rings. The polar high charge densities of DHPs and FL118 form stable hydrogen bonds with surrounding water molecules and stabilize the particle-solution interface. When FL-2NPs are triggered by endogenous reductive stimulation in the TME, they rapidly release the bioactive FL118 for anti-cancer therapy.

Guo and coworkers self-assembled the CPT derivative irinotecan with the photosensitizer CUR to develop a new dual-action anti-cancer drug.¹¹³ Although a variety of anti-cancer drugs inhibit tumors via distinct mechanisms, appropriate combinations can achieve synergistic effects for improved anti-tumor efficacy. An ion pair complex (ICN) composed of CUR and irinotecan hydrochloride in polar organic solvent displayed a dispersion stability time profile indicative of hydrogen bonds between CUR and its derivatives. This unique nanoparticle not only overcomes the hydrophobicity of CUR, but also enhances the anti-tumor effect of irinotecan by integrating multiple therapeutic modes. Similarly, Zhao and colleagues assembled the CPT analog 7-ethyl-10-hydroxycamptothecin (SN38) with the PDT compound Ce6, yielding the carrier-free nanoparticle SN38/Ce6 for combined chemical photodynamic therapy (CDT) against cancer.¹¹⁴ Both visual images of molecular dynamics simulations (MDS) and experimental data revealed that the main driving forces for self-assembly were hydrophobic interactions and van der Waals forces, which constitute a novel strategy for the development of NDDSs. The stability and dispersion of the SN38/Ce6 NPs were significantly improved compared to free Ce6 NPs. In addition, the compound demonstrated higher ROS production efficiency under irradiation and enhanced cell absorption and tumor accumulation in vivo and in vitro.

2.3.3. Paclitaxel. Paclitaxel (PTX), a natural alkaloid isolated from Taxus chinensis, is a first-line clinical chemotherapy drug with broad-spectrum effects against breast, ovarian, and non-small cell lung cancer among other neoplasms.^115,116 However, the complex chemical structure and numerous hydrophobic groups of PTX result in poor water solubility, which limits its clinical application.^117,118 Therefore, many NDDSs based on PTX or self-assembly of PTX prodrugs have been developed and used to improve the drug loading and targeting for enhanced efficacy. Paclitaxel can be coupled with hydrophilic PEG or amino acids to form amphiphilic prodrugs and self-assembled into nanoparticles.¹¹⁹ PTX can also form nano-assemblies through hydrophobic interactions with certain hydrophobic molecules in water. In addition, PTX can be self-loaded into nanodrugs by forming dimer prodrugs. Paclitaxel can form prodrugs with hydrophilic molecules, including various peptides. Amphiphilic peptide PTX prodrugs can self-assemble into nanoparticles in water.¹²⁰ Tian and colleagues designed and synthesized a cell-penetrating peptide (CPP)–PTX conjugate (CPP–PTX) and demonstrated that CPP–PTX self-assembled into PTX–CPP supramolecular nanospheres with a size of roughly 130 nm and a drug loading efficiency of up to 26.4%. Evaluation of the cytotoxicity on HepG2 cancer cells showed that the PTX–CPP nanospheres do not affect the activity of paclitaxel, and its cytotoxicity is almost equivalent to that of free drugs.¹²¹

An and colleagues¹²² designed a SANDDS that exploits the hydrophobicity of PTX to assemble gallic acid (GA)Fe(III)-coated bovine serum albumin (BSA) nanoparticles (GA-Fe@BSA-PTX) with a consistent size (∼115 nm), high water dispersibility and stability, and low non-target cytotoxicity. Moreover, GA-Fe@BSA-PTX demonstrated a good magnetic resonance imaging performance and tumor accumulation equivalent to GA-e@BSA-PTX. The self-assembled nanoparticles showed good therapeutic efficacy due to the combined effects of chemotherapy and photothermal therapy (PTT).

Amphiphilic molecules can easily self-assemble into nanoparticles in water, while hydrophobic molecules easily form precipitates in water and are difficult to self-assemble into nanoparticles. However, inserting disulfide bonds between two hydrophobic molecules can promote their self-assembly to form stable nanodrugs. Wang and colleagues conjugated the hydrophobic PTX and the hydrophobic vitamin E (VE) through an S–S bond to form the PTX-S-S-VE prodrug molecule and further showed its self-assembly into uniform and stable nanoparticles with a drug loading efficiency for Taxol of up to 60%.¹²³

Zhou and coworkers constructed a self-destructive dimer PTX prodrug connected by a hypoxia-sensitive azobenzene bond and used the dimer prodrug with Ce6 for combined chemotherapy and PDT, while exploiting the hypoxic characteristics of the TME for targeting.¹²⁴ When the drug reaches the hypoxic tumor site, the prodrug will undergo biological reduction due to the overexpression of nitroreductase and azoreductase, releasing active PTX. Simultaneously, the photosensitizer will produce ¹O₂ in response to light stimulation for further tumor cell destruction. This process requires oxygen consumption, which further aggravates hypoxia in the TME, and thus promotes the release of more dimer prodrug. Through this cycle, synergy is achieved for a superior anti-tumor effect.

Wang and colleagues reported that fluorination can further improve the self-assembly properties of PTX prodrug nano-assemblies.¹²⁵ A fluorine-modified prodrug was developed by combining PTX with perfluorooctanol (F8-SS-PTX) through disulfide bonds and compared to PTX octanol prodrugs (C8-SS-PTX). The results showed that fluoroalkylation can improve the self-assembly stability, in vivo fate, and anti-tumor efficacy. Fluorination may be an especially effective strategy for the rational design of advanced nanodrugs. This assembly process was further demonstrated by MDS, which revealed that alkyl–π interaction is the main force for C8-SS-PTX assembly given that there are more hydrogen bonds, while halogen bond formation (C=O⋯F) is the main force for F8-SS-PTX assembly. The only difference between these two prodrug nanomodules is the substitution of fluorine atoms. It has been reported that fluoroalkylation can promote the self-assembly of amphiphilic polymers and greatly improve the self-assembly and colloidal stability of prodrug nanomodules due to the fluorine-mediated hydrophobic force and the halogen bond of fluoroamphiphilic polymers.

2.4 Polyphenols

Polyphenols are organic molecules containing o-dihydroxy or o-trihydroxy groups directly connected to aromatic hydrocarbon groups by one or more hydroxyl groups. These structures are complex and diverse, and widely distributed in vegetables, fruits, spices, herbs, tea, and grapes among other sources.¹²⁶ The demonstrated benefits of these compounds include anti-inflammatory, anti-tumor, anti-vascular, antioxidant, and antibacterial bioactivities.¹²⁷ The distinct properties of these molecules, including antioxidant activity, anti-aging effects, substrate adsorption, adhesion, enzyme inhibition, and biocompatibility, appear to depend on the positions of various functional groups such as carbon–carbon double bonds, phenolic hydroxyl moieties, and carbonyl groups. In recent years, polyphenols have attracted extensive attention due to their excellent properties for various biomedical applications such as imaging and drug delivery.¹²⁸ Polyphenols can form metal polyphenolic networks (MPNs) by complexing with metal ions through coordination bonds. These MPN structures can be used to construct core–shell structures to transport hydrophobic drugs and can also improve the efficacies of protein drugs and inhibitors.¹²⁹ The polyphenols commonly used for self-assembly modification include tannic acid (TA), catechin (CA), epigallocatechin gallate (EGCG), oligomeric epigallocatechin gallate (OEGCG), and gallic acid (GA).¹³⁰

The catechol structure of natural polyphenol compounds can coordinate with a variety of metal ions, and the MPNs formed are important resources for new drug research.¹³¹ MPNs have attracted much attention in the drug research and development fields due to their simple fabrication, excellent physical and chemical properties, high biocompatibility, and numerous potential therapeutic applications.¹³² Drug delivery by MPNs has many advantages, including the potential for drug-controlled release, tumor metastasis inhibition, bioimaging, and tumor targeting. Through the coordination network, many types of drugs can be encapsulated for targeted release, and different types of capsules and films can be obtained by selecting different metals to construct MPNs, thereby expanding their functional diversity.¹³³ The selection of metal ions is also critical for effective tumor visualization. In addition, MPNs have good pH responsiveness. Acidic conditions can weaken the coordination between polyphenols and metals to achieve specific drug release in the TME, reduce exposure and toxicity to normal cells, and improve bioavailability. At present, MPNs composed of metal ions and polyphenols have aroused the interest of researchers due to their pH responsiveness, flexible structures for the incorporation of various small and macromolecules and good thermal stability. Currently, these systems are being used for the development of novel antibacterial drugs, anti-tumor therapies, PDTs, CDTs, and metal ion imaging.¹³⁴

2.4.1 Curcumin. Curcumin (CUR) is a flavonoid polyphenol extracted from the rhizome of Zingiberaceae and Araceae plants and is a natural photosensitizer.¹³⁵ In addition, CUR has documented anti-inflammatory, antioxidant, antibacterial, hepatoprotective, anti-cancer, and anti-angiogenesis activities. These pharmacological activities originate from the unique structures present in CUR such as β-diketone and dual phenyl, methoxy, and hydroxyl groups.¹³⁶ However, free CUR has poor water solubility, low bioavailability, and poor stability, properties, which limit its clinical applications. Nonetheless, CUR can be combined with a variety of substances to mitigate these shortcomings to produce more effective anti-tumor drugs.¹³⁷

Wang and colleagues synthesized multifunctional dendritic mesoporous nanoparticles (DMSNs) for carrying CUR through Ca²⁺ chelation (Cur-Ca@DMSNs-FA).¹³⁸ This carrier system demonstrated pH-sensitive drug release as well as good tumor cell targeting and biocompatibility. Cur-Ca@DMSNs-FA also induced apoptosis of breast cancer cells by inhibiting the PI3K/AKT/mTOR and Wnt/B-catenin signaling pathways and by activating the mitochondrial apoptosis pathway. Further, the carrier significantly improved the bioavailability of CUM in vivo. Thus, these initial findings provide a theoretical basis for the development of new drugs to treat breast cancer.

Chelation with metal ions can also be used to combine CUM with contrast agents for simultaneous tumor destruction and imaging application. Cancer cells have high energy requirements, and thus inhibiting mitochondrial respiration is a powerful means of cancer treatment. Recent studies have reported that CUM can inhibit mitochondrial function and induce endoplasmic reticulum stress in cancer cells, causing the release of Ca, which leads to the loss of mitochondrial membrane integrity, triggering of apoptosis.¹³⁹ Wen and colleagues¹⁴⁰ constructed Moss PNs with CUR and Gd³⁺ and loaded indocyanine green (ICG) through electrostatic attraction, yielding ICG@cur-GdNPs. The degradation properties of these NPs led to the specific release of CUR, Gd³⁺ and ICG in cancer cells, greatly improving the efficacy of chemotherapy/PDT, while minimizing damage to normal tissues. Curcumin has also been found to induce mitochondrial damage in cancer cells, while Gd³⁺ integration in ICG ICG@CUR-GdNPs allowed for magnetic resonance (Mr)/fluorescence imaging guided chemotherapy/PDT. Bimodal MR/fluorescence imaging using ICG@CUR-GdNPs may provide accurate tumor visualization to guide combined chemotherapy/PDT. Indeed, both in vivo and in vitro experiments have shown that this system has superior efficacy for the treatment of triple negative breast cancer.

Wong and colleagues found that CUR can complete self-assembly with sugar as the catalyst.¹⁴¹ When fructose and CUR are added to water, the hydrogen bonds of fructose can guide the self-assembly of the highly insoluble (hydrophobic) CUR to form a well-defined capsule through non-covalent forces. This simple method has the potential for template polymerization and construction of nanocarriers in water.

2.4.2 Tannic acids. Tannic acids (TAs) (general chemical formula C₇₆H₅₂O₄₆) are tannins obtained from Chinese gallnut with a large number of o-phenolic hydroxyl structures and catechol structures, which provide chelating sites for various metal ions, inducing the rapid self-crosslinking of polyphenols and facilitating the establishment of MPNs.¹⁴² The aromatic groups and hydroxyl groups of TAs can interact with many molecules through hydrophobic interactions and hydrogen bonding.¹⁴³ Xie and colleagues described the structure of these MPNs in detail.¹²⁷ The chelating sites provided by the adjacent hydroxyl groups in TA can react with various metal ions. The abundance of gallic groups in TA helps coordinate the crosslinking to produce three-dimensional stable MPNs.¹⁴⁴ These MPNs can also be used as a platform for tumor imaging, as drug-delivery carriers, and as drugs for PTT, radiotherapy, chemotherapy/PDT, and multimodal combination therapy.¹⁴⁵ Traditional therapeutic nanoplatforms often have complex nanostructures that require additional physical and/or chemical procedures for clinical use, which may increase their biological toxicity. In this case, the use of metal–phenol structures as nanoplatforms can greatly extend their blood circulation time, which can facilitate targeted treatment and imaging. New drugs developed with natural polyphenols can also better meet safety requirements in vivo. The development of MPNs has opened many new avenues for comprehensive cancer treatment regimens, including multimodal anti-tumor strategies combined with imaging feedback of therapeutic response. It is a long-term research task to develop new and multifunctional drug delivery systems, especially to stimulate the release of reactive drugs. Liu and colleagues¹⁴⁶ explored the pH responsiveness of polyphenols. Among the various types of drug-release stimuli, pH sensitivity has received the most attention from developers of anti-cancer drugs given that tumors have a highly acidic environment, and thus should trigger rapid drug release. The protonation of polyphenols under acidic conditions weakens the coordination between metal ions and polyphenols, endowing MPNs with highly pH-dependent decomposition and drug release properties. Therefore, nanoplatforms based on MPNs show unique advantages for cancer treatment.

Many protein drugs have demonstrated potent pharmacological effects, but have limited clinical utility due to their potential immunogenicity, high degradability, and rapid removal from the circulation.¹⁴⁷ In this case, PEG is widely used to improve the clinical utility of protein drugs, but some proteins cannot bind to PEG because they do not contain the necessary functional groups, such as amino, carboxyl, and mercaptan groups. In addition, PEGylation may reduce the activity of the original protein due to spatial interference at the active site. Alternatively, polyphenols are composed of hydrophobic and hydrophilic groups, which can form complexes with biological macromolecules such as proteins through non-covalent interactions. Honda and colleagues¹⁴⁸ modified a green fluorescent protein with TA to improve the stability of the protein delivery system. However, there was a non-specific interaction between the two, and thus they used a copolymer modified with tannic acid and PBA to conduct sequential self-assembly, mixed the protein and TA in aqueous solution to cover the protein with TA, and then added the copolymer PEG (PEG poly(amino acid)) to form borate esters between TA and the copolymer, yielding a core–shell ternary complex. In a subcutaneous tumor model, this ternary complex covered by PEG prevented adverse interactions with serum components, thereby significantly prolonging its blood circulation and enhancing its accumulation at the tumor site. This supramolecular self-assembly technique can be used as a new method to design protein delivery systems.

In recent years, hollow capsules assembled with MPNs have attracted interest due to their ideal performance, selective permeability, high mechanical and thermal stability, and pH-responsive decomposition. Guo and colleagues developed a library of MNP capsules with distinct properties by combining TA with different metal ions.¹⁴⁹ For example, the film thickness, disassembly characteristics, and fluorescence behavior were all dependent on the metal ions. In addition, customized functions such as drug delivery, suitability for positron emission tomography and magnetic resonance imaging, and catalysis can be introduced through the selection of the appropriate TA/metal combination. For instance, the thickness and stability of the MPN film was controlled by metal selection and the metal feed concentration. The intermediate disassembly kinetics of the Al³⁺-TA capsules compared with Cu²⁺-TA capsules and Zr⁴⁺-A capsules was consistent with the ideal drug-delivery profile because the capsules were relatively stable at the blood pH (7.4) and gradually disassembled in lower pH regions such as lysosomes (pH of 5.0–6.0). Moreover, the Al³⁺-TA capsules showed extremely low cytotoxicity and better-controlled release potential. The addition of 2-monoacyltrifluoroacetone (TTA) and acetylacetone (AA) to the EuIII-TA and TbIII-TA networks enhanced the imaging characteristics of MPN capsules for use in tracking the biological distribution of the loaded drug and the carrier itself. The authors also assembled (CuII/UuIIITTA)-TA capsules and studied the function of mixed bimetallic capsules as biomedical imaging agents. Analysis using X-ray photoelectron spectroscopy confirmed that electrons were transferred from TA to metal, and also confirmed the coordination between TA and metal. Thus, the addition of a variety of metals to MPN capsules can produce a variety of functional materials and clinically useful properties.

Ping and coworkers studied the pH response of MPN capsules designed as self-assembled film of TA and Al³⁺ to support the anti-cancer drug DOX using PSS-doped CaCO₃ as the template and demonstrated that the obtained DOX-AlIII-TA showed a good drug loading ability and pH response as well as reduced non-target cytotoxicity and improved tumor targeting.¹⁵⁰ The formation of coordination bonds between polyphenols and Al³⁺ is pH dependent, and these bonds also exhibit pH-dependent decomposition. Simulation of the pH environment inside and outside cells and in lysosomes revealed that the DOX-AlIII-TA capsule stability was reduced at acid pH values. Also, the permeability of the DOX-AlIII-TA capsule allowed free DOX to diffuse through its permeation shell due to the reduced hydrogen bond interaction between DOX and poly(styrene) sulfonate (PSS), and the increased hydrophilicity of DOX at low pH. This characteristic reduces the cytotoxicity in the circulation and strengthens the targeting.

Ejima and coworkers reported a simple, rapid, and robust conformal coating method involving the one-step assembly of coordination complexes to prepare various films and particles.¹⁵¹ Natural polyphenol tannic acid (TA) and FeIII were used as the organic ligand and inorganic crosslinking agent, respectively. This force of X depended on the adsorption capacity of polyphenols and was guided by pH-dependent multivalent coordination bonds. The three tolylpropyl groups in TA can react with each FeIII ion to form a stable octahedral complex, enabling each TA molecule to react with several FeIII centers to form a cross-linked film. TA has a general surface binding affinity, and thus this method is applicable to a variety of substrates. This film can cover substrates with different compositions, sizes, shapes, and structures in a conformal manner, and can even be used to produce hollow capsules. This system has extensive applications in drug and gene delivery as well as catalysis and biosensors.

Rahim and colleagues used metal polyphenol interactions to form a surface-restricted film, especially between tannic acid and Fe³⁺.¹⁵² They demonstrated a simple, rapid, and universal strategy for the formation of surface-confined films. These molecular hybrid films may provide a wide range of multifunctional platforms, including catalysis, energy, and optoelectronics, and the experimental results demonstrated that the presence of at least one adjacent diol group (i.e., double dentate) in the aromatic ring is a prerequisite for membrane formation (phenolic ligands).

2.4.3. Other polyphenols. The polyphenols in tea are reported to have anti-inflammatory, anti-tumor, vasodilator, antioxidant, chemopreventive, and antimicrobial activities.¹⁵³ In addition, tea polyphenols have a wide range of applications in self-assembly.¹⁵⁴ For instance, epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG), have been used for the development of many new drug delivery systems.¹⁵⁵

EGCG is the main component of green tea polyphenols and catechin monomer isolated from tea leaves and has documented antibacterial, anti-viral, antioxidant, anti-atherosclerosis, anti-thrombosis, anti-angiogenesis, anti-inflammatory, and anti-tumor effects.^156–158 EGCG molecules, with galloyl and catechol groups, can interact non-covalently with various biological molecules such as DNA and RNA to form complexes for synergistic therapy. However, EGCG is hydrophilic, while many anti-cancer drugs are hydrophobic, and thus it is difficult to directly load anti-cancer drugs onto EGCG. Ding and colleagues assembled EGCG, (si)RNA, and protamine sulfate into a nanogel carrier for siRNA.¹⁵⁹ The siRNA/protamine complex was first formed into a dense nanocomposite via the electrostatic interaction of the positively charged protamine sulfate, and then the anti-cancer drug EGCG was absorbed through non-covalent interaction with siRNA. To prevent drug leakage, simultaneously HA was assembled into siRNA/EGCG/protamine nanocomposites. The carrier showed good drug loading and used an HA shell and tumor homing cell-penetrating peptide as target ligands, which has minor side effects. This design effectively overcomes the drug resistance problem caused by the overexpression of connective tissue growth factor in breast cancer and provides a template for further drug development for drug-resistant triple negative breast cancer.

Polyphenols can also inhibit the epithelial to mesenchymal transition, downregulate the expression of vascular endothelial growth factor and matrix metalloproteinases (MMP) levels, and regulate other molecular pathways. Based on these properties, polyphenols can be used as anti-tumor metastasis adjuvants to compensate for the limitations of chemotherapy.^160,161 In this case, EGCG is the most effective polyphenol against tumor metastasis. Chen and colleagues developed a multifunctional drug-delivery system, EINP@DOX, composed of tea-derived polyphenol EGCG, iron ion, and DOX.¹⁶² The driving force for the formation of the EGCG iron nanoparticles (EINP) is the coordination bond rather than ionic, hydrogen bond, or hydrophobic interaction. Experimental tests revealed that EINP@DOX has good stability under physiological conditions and can be rapidly decomposed in acidic environments such as nuclear endosomes. This system integrates the functions of treatment, imaging, and anti-metastasis for systematic tumor treatment. In vitro and in vivo studies demonstrated its good tumor diagnostic performance and curative effect, including effective inhibition of metastasis.

Skin melanoma is one of the most lethal and fastest growing cancers in humanins. Li and colleagues designed a self-assembled Sm³⁺-EGCG nanocomposite with synergistic tumor inhibition properties by chelating EGCG with Sm³⁺.¹⁶³ In a murine model, Sm³⁺-pigallocatechin-3-O-gallate effectively induced the apoptosis of melanoma cells through mitochondrial dysfunction, and also effectively inhibited metastasis to other major organs, which is the ultimate cause of mortality from advanced melanoma.

Bortezomib (BTZ) is a boric acid protease inhibitor used for cancer treatment, but its efficacy may be reduced by combining it with polyphenols in food. Thus, to solve this problem, Wang and colleagues constructed a supramolecular nanosystem to achieve drug-controlled release.¹⁶⁴ They combined BTZ with natural catechol-containing polyphenols through borate ester bonds, formed dynamic drug amphiphiles through catechol–boric acid dynamic covalent bonds, introduced iron ions into supramolecular system for biological imaging and improved the molecular stability, yielding a new drug termed BTI. This agent demonstrated pH-dependent cytotoxicity by releasing BTZ, while significantly reducing the cytotoxicity of free BTZ. Studies have shown that supramolecular nanodrugs composed of natural polyphenols, BTZ, and iron ions can induce cancer cell apoptosis and inhibit tumor growth with fewer adverse reactions. This unique supramolecular design provides many advantages for the treatment of tumors, including highly efficient and accurately controlled drug loading, excellent biodegradability and biocompatibility, easy preparation, and simple chemical synthesis. The resulting BTI supramolecular nanodrugs have high biocompatibility with blood and normal tissues and can enhance the anti-tumor therapeutic effect of BTZ, which is especially useful for the treatment of bone tumors.

Zhang and colleagues designed another targeting drug through the self-assembly of bovine serum albumin (BSA) and tea polyphenol (TP), yielding nanospheres, which were then modified with folic acid (FA) to support doxorubicin, ultimately yielding DOX@BSA-TP-FA.¹⁶⁵ The cysteine and sulfhydryl structure of NSs and BSA allow for glutathione targeting in tumor regions, while the DOX@BSA-TP-FA folic acid on the surface of NSs can bind to the folate receptor on the surface of tumor cells, which improves the drug targeting. Overall, this system demonstrated efficient drug loading, further supporting its possible clinical application.

Chung and coworkers composed self-assembled micellar nanocomposites of green tea catechin derivatives and protein drugs and demonstrated that both drugs have therapeutic effects equivalent to the corresponding carrier-free drug.¹⁶⁶ Oligomeric EGCG derivatives were self-assembled with the anti-cancer protein Herceptin to form stable micelles and complexed with PEG-EGCG to form a shell. The assembled complex showed better tumor selectivity and growth suppression, a longer blood half-life, and better biocompatibility than the original protein. The prevention of Herceptin clearance not only improved the drug efficacy but also effectively reduced the carrier toxicity.

Anti-cancer drugs based on cisplatin often induce resistance and strong side effects, while anti-cancer drugs delivered through MPNs are generally less prone to resistance due to their synergistic actions and produce fewer side effects due to their superior tumor targeting. Dai and colleagues assembled polyphenols and cross-linked iron ions to form MPNs and coated (PEG)-modified Pt prodrug to deliver cisplatin drugs.¹⁶⁷ In a mouse experiment, platinum nanoparticles showed better tumor inhibition than the equivalent dose of free platinum prodrug with no obvious side effects.

Compared to nanowires, nanoparticles, and nanosheets, flower-shaped nanomaterials (nanoflowers) have demonstrated several advantages as drug-delivery vehicles, including a larger surface area for drug loading and release as well as excellent catalytic ability. Xu and Liu et al. oxidized tea polyphenols in air to obtain tea polyphenol palmitate (TPP), and then self-assembled TPP with copper sulfate to form nanoflowers.¹⁶⁸ Thorough characterization of the product revealed that the TPP oligomer was strongly coordinated with Cu²⁺. Tea polyphenol hybrid nanoflowers also possessed a flower-like porous structure and hydrophobic bags provided by lipophilic side chains, which conferred high CUR loading capacity and a demonstrated a robust pH-dependent drug release response. The nanoflower also protected CUR from ultraviolet radiation and heat treatment. Through derivatization and oxidative coupling of tea polyphenol components, the assembly behavior could be easily adjusted to produce particles with substantial structural versatility.

However, controlling the self-assembly process in a multicomponent environment remains a challenge. Lin and coworkers produced a metal phenolic network by adding Fe³⁺ into the solution of eucalyptus leaf extracts containing multiple phenolic compounds¹⁶⁹ and found that the number of chelating sites on the phenolic compounds may determine the selective assembly observed in complex multicomponent systems. As the reaction proceeds, the target ligand with two chelating sites can grow and form a large scalable network. Surface adsorption and simultaneous crosslinking are more competitive if there are more sites in this network compared to those with fewer chelating sites. The selective metal–phenol assembly can recognize the small change in the number of possible chelating sites between different phenolic compounds, which makes it a simple method to separate required phenolic components from complex systems. In addition, MPNs and free phenolic compounds show a better free radical scavenging performance, making them potential candidates for antioxidant applications.

2.5. Saponins

Saponins are abundant in terrestrial plants such as Ginseng, Polygala tenuifolia, Platycodon grandiflorum, Glycyrrhiza, Anemarrhena asphodeloides and Bupleurum chinense.^170,171 Common saponins with demonstrated pharmaceutical activities include ginsenoside from ginseng, GA from licorice, and platycodon from Platycodon grandiflorum. These compounds are used as antipyretics, sedatives, anti-cancer agents, and for the treatment of diabetes, depression, and other disorders.^172–174

Saponins are composed of aglycones and glycosides, and the specific structures and functional groups of these two components confer unique bioactivities.¹⁷⁵ More than 100 ginsenosides have been described and investigated for pharmaceutical activities. These studies have found that most saponins with anti-cancer activity have fewer sugar groups, and thus low water solubility and bioavailability, which abrogates the unique advantages of these natural drugs. Saponins are natural surfactants due to their unique amphiphilic structure. The sugar chains of saponins have strong hydrophilicity, while the core sapogenin has strong lipophilicity. Therefore, similar to other synthetic surfactants, saponins have high surface activity and self-assembly performance, and can be used as natural drug carriers.¹⁷⁶ It is undoubtedly a good strategy to encapsulate anti-cancer NSMs through simple synthesis to improve their poor physical and chemical properties. Compared to synthetic carriers, NDDSs based on saponin compounds have unique targeting and improved biological drug resistance, features that enhance their tumor cell toxicity. Compared to synthetic carriers, saponins also demonstrate higher safety and stability, are less toxic due to reduced carrier accumulation, and show better metabolic clearance. Therefore, saponins are a good choice for the construction of liposome drug-delivery systems.^177,178

2.5.1. Ginsenosides. Ginsenosides (GSs) are a group of ginseng-derived compounds¹⁷⁹ with bioactivities against diabetes, cancer, depression, cerebral ischemia, endothelial cell injury, and cardiovascular diseases among others.¹⁸⁰ Ginsenosides are used extensively in the development of anti-cancer drugs given that they have been shown to reduce multidrug resistance and improve the anti-tumor effect through synergy with other drugs. GSs are divided into four types, i.e., panaxadiols (PPDs), protopanaxadiols (PPTs), OAs, and C17 side chain variation types (C17SCVs), according to the way in which the sugar chain is covalently linked with triterpene aglycones through glycosidic bonds, and among them, PPDs and PPTs are the two most widely investigated types.^181,182 The PPD types, including GS Rb1, Rg3, Rh2, and compound K (CK), mainly bind sugar groups at C-3, and PPTs such as GS Re, Rg1, and Rh1 combine with glycosyl primarily at C-6, while Rg5 belongs to C17SCVs. Ginsenosides are the most common saponin types¹⁸³ and usually contain a fixed dammarane skeleton with 17 carbon atoms in four rings. This steroid skeleton leads to low water solubility, although the solubility of individual compounds is modified by glycosyl binding at the C-3, C-6, and C-20 positions.^184,185

GSs have unique advantages for cancer treatment, but their poor water solubility severely limits their application.¹⁸⁶ In this case, the development of SANDDS allows for a variety of GS applications. Amphiphilic GS can be self-assembled in aqueous solution to form unique core–shell structure nanoparticles, with hydrophobic chambers formed in the middle to transport hydrophobic drugs with improved solubility and stability.^187,188 The unique characteristics of GS can improve the sensitivity of tumor cells to taxanes, and the glucose analogs in this structure can combine with glucose transporter-1 (GLUT1) on the surface of cancer cells to enhance targeted drug delivery.¹⁸⁹ GSs can assemble into spherical nanoparticles (GSN) with an average diameter of 18.24 nm through hydrogen bonding and hydrophobic interactions between GS and anti-cancer drugs in aqueous solution. A hemolytic test indicated that GSN has good biocompatibility and biosafety (Fig. 7). In vitro, free GS exhibited higher cell toxicity to normal cells than GSN, which also indicated the relative biosafety of GSN. In vivo, GSN showed significant inhibitory effects on cancer metastasis with an H22 murine artificial pulmonary metastatic model.¹⁹⁰ Similar to many other TCM ingredients, GSs have strong pharmacological effects but low water solubility, poor stability and low bioavailability. However, it is often possible to improve their physical and chemical properties and enhance their solubility by coupling these molecules to hydrophilic compounds, such as bovine serum albumin (BSA), PEG, and chitosan derivatives.

Fig. 7 Schematic illustration of the process for the preparation of GSN and its anti-metastasis activity. Reprinted with permission from ref. 190. Copyright (2022), Elsevier.

Alternatively, wrapping hydrophobic anti-cancer drugs in GS as a carrier can improve the solubility of both components and facilitate synergistic anti-tumor efficacy. Dai and colleagues proposed a universal hydrophobic drug-delivery system with GS as the carrier and encapsulated anti-cancer drugs to form nanoparticles through the unique self-assembly characteristics of GS.¹⁹¹ In this simple manufacturing process, hydrophobic drugs were encapsulated by the hydrophobic triterpene group of GS Rb1 NPs. The core can be used as a nanocontainer for hydrophobic drugs, and the shell can be formed by the sugar chains of GS to improve the water solubility and stability. Further, GS Rb1 itself has a variety of biological activities, including anti-cancer, antioxidant, and anti-inflammatory effects, inhibition of neointima hyperplasia, induction of angiogenesis, and vasodilation. Thus, the carrier itself can contribute to the therapeutic effect. Most importantly, it has good biosafety. In addition, the GS core–shell structure obtained by this method has the advantages of easy preparation, appropriate size, better tumor selectivity, efficient drug loading capacity, and good stability.

Ginsenoside-based drug-delivery systems also possess unique penetration characteristics. For instance, insulin (INS) is the first-line treatment for type 1 diabetes. However, traditional insulin administration requires frequent subcutaneous injection and can induce periodic hypoglycemia as well as fat atrophy, local tissue necrosis, nerve damage, and other diseases over the longer term. Transdermal drug delivery is an alternative that may mitigate these effects by supplying a more constant dose. Further, compared to subcutaneous injection, transdermal patches can improve patient compliance and avoid the gastrointestinal “first pass” metabolism following oral administration. Zou and colleagues developed a new nanopreparation consisting of insulin and GS for transdermal administration, namely, INS@GSNPs,¹⁹² which can pass through the cutin barrier in the skin. The system is self-assembled into a spherical shell structure through hydrogen bonding and both hydrophobic and electrostatic interactions. Ginsenoside is assembled into a shell to protect insulin from hydrolysis and improve its stability. The natural steroid structure of GS enhances the skin penetration given that the unique interactions between ginsenosides and membrane components such as cholesterol and phospholipid produce temporary pores. Further, experimental testing revealed sustained release characteristics and good hypoglycemic efficiency.

Dai and colleagues also¹⁹³ studied the self-aggregation behavior of ginsenoside Ro (Ro) and the interaction between Ro and saikosaponin a (SSa) through mesoscopic simulations and dissipative particle dynamics, and further explained the mechanism of saponin aggregation and dissolution from different views as well as the principle of SSa solubilization by Ro. Ginsenoside Ro is a bimolecular saponin with two sugar chains connected to a triterpene aglycone. This special triblock copolymer-like structure enables the self-assembly of Ro in aqueous solution. MDS results showed that Ro can form spherical vesicles in aqueous solution with two hydrophilic regions, i.e., one in the core and the other on the surface, to obtain good carrier capacity for hydrophobic drugs. In contrast, the glucuronic acid component of Ro was located on the surface of the vesicle, where it was stabilized by strong hydrophilicity and electrostatic repulsion. At low concentrations, SSa molecules were found to dissolve in the palisade layer of Ro vesicles and the hydrophobic aglycone of the SSa molecule was inserted into the transition layer formed by the aglycone of Ro, while the SSa sugar was located on the surface and interacted with the Ro sugar through hydrogen bonds or dipole interactions. At higher SSa concentrations, Ro interacted with SSa to form mixed vesicles. Due to its stronger hydrophobicity, SSa molecules were preferentially absorbed by vesicles closer to the core. This study demonstrated for the first time that Ro can form vesicles through the closure of a flat layer membrane, a finding that broadens our understanding of the GS self-assembly behavior and may also expand the potential applications of GS in the construction of NDDSs.

Coupling saponins with hydrophilic molecules is also an effective method to improve their water solubility. Moreover, the polymers obtained through coupling often have strong self-assembly ability, which is conducive to drug delivery. Ginsenoside compound K (CK) is one of the main metabolites of PPD-type GS after intestinal enzyme metabolism. It has a wide range of pharmacological properties, such as anti-cancer, neuroprotective, anti-inflammatory, anti-angiogenesis, anti-allergen, anti-diabetes, anti-aging, and hepatoprotective activities. However, its low water solubility and poor permeability reduce its clinical efficacy.^194,195 Mathiyalagan coupled CK to the backbone of the hydrophilic glycolchitosan (GC) through self-assembly to form spherical GC-CK nanoparticles in aqueous solution.¹⁹⁶ Glycolchitosan has low toxicity and good biocompatibility, and thus can be used as a multifunctional carrier to deliver therapeutic drugs efficiently. The combination of anti-cancer drugs with hydrophilic polymers can increase the half-life of drugs in vivo and their anti-tumor effect. In this study, GC-CK was constructed to improve the drug solubility and anti-tumor efficacy, prolong blood circulation time, and protect against proteolysis. Zhang and colleagues¹⁹⁷ synthesized deoxycholic acid-O carboxymethyl chitosan (DA-OCMC) for the encapsulation of CK into NPs by combined ultrasonic dialysis and self-assembly technology. The negatively charged OCMC was uniformly distributed on the spherical surface of the CK NPs as a hydrophilic shell layer. This method greatly improved the solubility of CK, and the anti-cancer activity was also enhanced by the chitosan structure, which endowed greatly enhanced drug release efficiency under slightly acidic conditions (such as in the TES) and reduced the systemic toxicity. In vivo and vitro experiments showed that the tumor cytotoxicity and apoptosis rate were greatly improved compared to free CK.

Ginsenoside Rg5 (Rg5) is a rare ginsenoside with unique biological characteristics, which has demonstrated curative effects against esophageal, gastric, breast, and cervical cancers.¹⁹⁸ However, its clinical application is limited by its low water solubility, poor bioavailability, and short biological half-life. Dong and colleagues combined BSA with Rg5 by dispersing BSA in water, adjusting the pH to alkaline, and dehydrating Rg5 with ethanol to obtain a Rg5–BSA mixture, and then modified the surface BSA with folic acid to obtain FA-Rg5-BSA, a complex that improved the disadvantageous physical and chemical properties of Rg5.¹⁹⁹ In addition, the complex demonstrated good stability over a wide range of temperatures, specific release in the weakly acidic TME, and potent induction of MCF-7 cell apoptosis. In summary, this drug-delivery system has potential to markedly improve the clinical efficacy of Rg5.

The use of water-soluble polymers is another method for improving the poor water solubility and bioavailability of GS. Mathiyalagan and coworkers conjugated hydrophilic PEG to the surface of protopanaxadiols (PPD) through a pH-sensitive ester bond to obtain PEG–PPD.²⁰⁰ Due to the internal hydrophobicity and external hydrophilicity of the polymer, these conjugates spontaneously formed SANDDS in an aqueous environment. In this formulation, PEG improved the water solubility, targeting, and bioavailability of GS, while reducing the cytotoxicity to non-targeted tissues. In addition, PEG protected PPD from proteolysis and greatly prolonged the drug circulation time compared to free PPD. Moreover, the PEG–PPD self-assembled nanoparticles demonstrated robust pH responsiveness, enabling their effective accumulation at pathophysiological sites.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. The most common cause of mortality is not the tumor itself, but complications of chronic cirrhosis, such as ascites, hepatic encephalopathy, variceal bleeding, and hepatorenal syndrome. Thus, by inhibiting these complications, the survival time of patients can be greatly prolonged. Ren and colleagues synthesized Fe@Fe₃O₄ nanoparticles conjugated with GS Rg3 (Rg3) (NpRg3) through self-assembly and found that they effectively inhibited HCC development and metastasis. Metal and metal oxide nanoparticles have good therapeutic functions, and iron-based nanoparticles have excellent biocompatibility and liver-targeting properties.²⁰¹ Studies have shown that NpRg3 has good therapeutic effects on HCC complications. The application of NpRg3 also helps correct imbalances in the intestinal microbiota and metabolism during HCC treatment, can effectively inhibit HCC metastasis, and solve the problems of rapid gastrointestinal passage of Rg3 and its low liver absorption. Thus, the application of NpRg3 significantly prolonged the survival time of HCC model mice, inhibited the development of HCC, and eliminated metastasis of HCC to the lungs.

Liposomes are special nanocarriers that can improve the therapeutic efficacies of many different drugs.^202,203 Liposomes demonstrate EPR effects and can preferentially deliver therapeutic drugs to the tumor site, thereby enhancing the therapeutic efficacy and reducing systemic toxicity. However, to date, no liposome delivery system has been fully approved by the United States Food and Drug Administration (FDA). Replacing cholesterol synthesized in liposomes with ginsenoside compounds can obviate some of the inherent dangers of liposome delivery systems, such as hyperlipidemia, pulmonary hypertension, and other diseases caused by excessive cholesterol absorption.^204,205 Therefore, liposome delivery systems based on GS provide expanded possibilities for the delivery of liposome drugs for chronic diseases. Wang and colleagues conducted a detailed study of a ginsenoside delivery system, including a comparison of different GS types for encapsulation efficacy and the feasibility of preparation technologies.¹⁸⁴ They concluded that GSs are good pharmaceutical excipients to develop new drugs. In addition to excellent biological activity, GSs can stabilize the amphiphilic structure of phospholipid bilayers due to their structural similarity with cholesterol. Ginsenosides Rg3, Rg5, and Rh2 can replace cholesterol in liposomes carriers, and these new liposome carriers have demonstrated improved drug solubility, reduced drug toxicity and side effects, improved drug stability, increased free drug concentration in the vascular system, and prolonged circulation time. In addition, this new liposome delivery system had high tumor-targeting efficiency due to the biological activity of ginsenoside itself, as well as a synergistic effect with chemotherapy drugs. Thus, this new liposome drug-delivery system may effectively overcome the side effects of traditional cholesterol-containing liposome drugs, while reducing the systemic toxicity caused by non-targeted aggregation. Also, further improvements in liposome drug-delivery systems are likely in the near future.

Wang and colleagues designed a new liposome delivery system for tumor targeted therapy that solved a series of problems by replacing cholesterol with ginsenoside Rh2 (Rh2) to obtain PTX-Rh2-lipo, in which Rh2 is not only used as a membrane stabilizer, but also as a chemotherapy adjuvant.¹⁷⁸ Aglycones have a similar steroid structure to cholesterol, and thus can effectively replace cholesterol in the lipid delivery system. They have similar capacities to improve the physical and chemical properties of the phospholipid bilayer, which can effectively prevent allergic reactions to cholesterol and increase acceptance by vegetarians. In addition, Rh2(20 (S) – Rh2) can trigger a variety of signal transduction pathways to facilitate multiple synergistic anti-tumor mechanisms, including when loaded with the anti-cancer drug paclitaxel. However, because Rh2 is easily degraded in the gastrointestinal tract and blood, its bioavailability can be greatly enhanced by constructing a liposome delivery system. In vitro and animal model studies demonstrated that PTX-Rh2-lipo possesses good encapsulation and drug protection efficacy compared to traditional liposomes, with greatly prolonged drug circulation time and targeted release in the TME for improved treatment efficacy.

Triple-negative breast cancer continues to result in high mortality, with the proliferation of circulating tumor cells (CTCs) the main cause of death. Thus, Xia and colleagues proposed an improved liposome to assemble phospholipid, Rg3, and docetaxel (DTX),²⁰⁶ a first-line anti-metastasis drug approved by the FDA as an anti-cancer drug in 2000. This system effectively increased the tumor cell sensitivity to taxanes, thereby improving the anti-cancer efficacy. Through the structural analysis of Rg3, the authors found that its steroid ring structure, the side chain of C17, and the hydroxyl group of C3 site meet all the conditions required for the regulation of the liposome membrane proposed by researchers, which supports the potential of ginsenoside to replace cholesterol as a liposome membrane material. Ginsenoside Rg3 can be inserted into the liposome membrane and interact with phospholipids. The end pyran ring of the Rg3 hydrophilic group extends out of the phospholipid membrane plane and interacts with water in the solvent to reduce the mutual aggregation of water molecules. The hydroxyl group in the pyran ring of Rg3 can form a hydrogen bond with the amino group on the head of choline phosphate (PC), which increases the stability of the membrane and enables it to target and capture circulating tumor cells (CTCs). Compared to traditional liposomes and DTX micelles, the therapeutic effect of the drug was also significantly improved.

Zhu and colleagues used GS liposomes loaded with PTX for the treatment of glioma. Due to the multiple functions of G-Rg3, these liposomes not only effectively solved cholesterol-related obstacles, but also enhanced the BBB penetrability, GLUT-mediated active tumor targeting through immune enhancement, tumor cell killing activity, and TME remodeling.²⁰⁷ As shown in Fig. 8(A), ginsenoside Rg3 substitutes cholesterol as the membrane material in the preparation of Rg3-PTX-LPs. The glucose chains of ginsenoside Rg3 specifically bind to the GLUT of BBB and enhance the penetration of liposomes into the brain across the BBB. As shown in Fig. 8(B), Rg3-PTX-LPs target TAMs, promoting the normalization of M2 to M1 and eliciting anti-tumor immunity. Fig. 8(C) shows the release of the loaded drugs of Rg3-PTX-LPs and the induction of apoptosis of tumor cells. In vitro, the uptake of Rg3-PTX-LPs in C6 cells, BCEC and HUVEC cells was significantly higher than that of the common liposomes. Rg3-PTX-LPs could increase the penetration ability of BBB, promote tumor cell apoptosis, and extend the median survival time of glioma-bearing mice and rats from 27 days in the free PTX group to 54 days and 66.5 days, respectively. Rg3-PTX-LPs significantly improved the therapeutic effect on glioma. In addition, Rg3-based liposomes synergistically enhanced the chemotherapy efficacy of PTX, regulated the TEM, and activated the glioma immune microenvironment, significantly improving the anti-tumor effect.

Fig. 8 Schematic illustration of ginsenoside Rg3-based liposomes for glioma-targeting therapy. (A) Ginsenoside Rg3 substitutes cholesterol as the membrane material in preparing Rg3-PTX-LPs. (B) Rg3-PTX-LPs target to TAMs, promote the normalization of M2 to M1. (C) The apoptosis of tumor cells. (D) Rg3-PTX-LPs reduce the T-reg cells and MDSCs. Reprinted with permission from ref. 207. Copyright (2021), Elsevier.

The clinical treatment of gastric cancer (GC) is hindered by the development of anti-cancer drug resistance, poor pharmacokinetics, off-target toxicity, and insufficient accumulation of current chemotherapy drugs in the tumor. Hong and colleagues synthesized liposomes with GS replacing cholesterol to carry paclitaxel. Three formulations were obtained, PTX-Rh2-lipo, PTX-Rg3-lipo, and PTX-Rg5-lipo, by replacing cholesterol with Rh2, Rg3, and Rg5, respectively,¹⁷⁷ and their functions were compared, including blood circulation time, active recognition of GLUT1, and tumor cytotoxicity, to identify the most feasible for clinical treatment. The GS-containing liposomes have multiple functions in this new drug-delivery system, acting to stabilize the phospholipid bilayer and to promote the anti-tumor effects of PTX through synergy. Indeed, GS improved the therapeutic effect and enhanced the accumulation of liposomes at the tumor site, possibly by interacting with GLUT1. The main difference between liposomes with cholesterol or GS is the extra glycoside chain, which significantly changes the physical and chemical properties of the membrane. Compared to cholesterol, the addition of the hydrophilic glycoside chain significantly reduces the lipophilicity of ginsenoside, resulting in a significant difference in size and surface morphology (but not shape). In vivo and in vitro studies revealed that the blood circulation times of Rh2-lipo and Rg3-lipo were significantly prolonged compared to PTX-Rg5-lipo and cholesterol-based liposomes. The longer blood circulation time not only improved the stability and biological half-life of various components, but also exploited the passive targeting characteristics conferred by tumor blood vessels. Thus, compared to free Rh2 and Rg3, the ginsenoside liposomes also significantly enhanced tumor cell apoptosis, and the PTX leakage from PTX-Rh2-lipo and PTX-Rg3-lipo was only 25% after 48 h, indicating the good drug protection. Therefore, this liposome delivery system constructed with Rh2 and Rg3 can be an effective chemotherapy treatment.

2.5.2. Other saponins. Saponins possess a variety of physical and chemical properties and biological activities, and thus require individual study. Glycyrrhetinic acid (GA) is widely used in the pharmaceutical industry²⁰⁸ and its source plant (licorice) is an important medicinal material in TCM formulas.²⁰⁹ It is often assumed that the small molecules separated from the corresponding main drug have limited clinical applications. However, it is also possible that these compounds act synergistically with GA. For instance, studies have shown that GA in licorice promotes the absorption and utilization of other natural molecules.²¹⁰ The chemical structure of GA consists of one hydrophobic glycine and two hydrophilic glucuronic acids. In the absence of electrolytes, GA micelles are mainly slender rod-like structures, while the addition of electrolytes promotes the moderate growth of micelles with well-described natural surface activity. Tucker and coworkers²¹¹ studied the self-assembly characteristics of GAs in detail and found that saponins can self-assemble into a spherical, slender core–shell structure with an inner hydrophobic core and hydrophilic outer shell due to the presence of sugar side chains. The head base structure plays an important role in the self-assembly of saponins, while the number and size of sugar groups contribute to determining the micelle shape. A larger head base structure often confers greater curvature; thus, smaller spherical structures result when self-assembly is used to form micelles. Different electrolytes have different effects on the formation of micelles. In the presence of sodium chloride, magnesium chloride, and citric acid, the growth of micelles is relatively mild, which can promote the formation of a gel.

Glycyrrhetinic acid and GS can both self-assemble into spherical nanoparticles to carry other drugs and in fact have many similar self-assembly applications. You and colleagues used GA nanoparticles to improve the oral bioavailability of the polyphenol BAI,²¹² the main bioactive components of Radix Scutellariae with documented neuroprotective, antioxidant, antibacterial, anti-viral, anti-allergic, anti-inflammatory, and anti-tumor activities. The three adjacent phenolic hydroxyl groups in BAI form intramolecular hydrogen bonds, and thus the water solubility of BAI is low, resulting in its low oral bioavailability. The main purpose of wrapping BAI with GA is to improve its water solubility. Furthermore, to improve the bioavailability of BAI, nanomicelles with hydrophobic inner cavities were prepared via the self-assembly of amphiphilic molecular GA in aqueous solution. Hydrophobic cavities of nanomicelles can form host complexes by self-assembly to encapsulate other hydrophobic compounds including BAI, thereby increasing its solubility and inhibiting its precipitation. GA can also change the characteristics of the cell membrane to enhance drug absorption. The formation of this composite micelle is likely to be driven by hydrophobic and hydrogen bonding interactions. Thus, the formulation of GA-based micelles is a promising strategy to improve the bioavailability of NSMs.

In professor Di Liuqing's team from Nanjing University of Traditional Chinese Medicine, immune exosomes loading self-assembled nanomicelles (CpG-EXO/TGM) were constructed for chemo-immunotherapy against glioblastoma (Fig. 9).²¹³ Firstly, tanshinone II A (Tan II A), a lipid-soluble active component in Salvia miltiorrhiza, and glycyrrhizic acid (GL), an amphiphilic active component in TCM licorice, were used to construct Tan II A-GL micelles (TGM) through the self-assembly strategy. Then, TGM was loaded into the serum-derived EXO. Finally, CpG ODN 1826 was coupled to phospholipid DSPE and modified on the EXO membrane, and CpG-EXO/TGM was obtained for achieving the co-delivery of multiple components of traditional Chinese medicine and immune adjuvants. In cell experiments, this study demonstrated through confocal microscopy and flow cytometry that CpG-EXO/TGM is very easy for bEnd.3 cells and GL261 cells to uptake. After intravenous injection of CpG-EXO/TGM, the transferrin receptor on its surface can bind to free transferrin in the blood, and then cross the BBB/BBTB and enter cells through TfR-mediated endocytosis. In vivo, CpG-EXO/TGM could significantly prolong the median survival of orthotopic glioma mice and inhibit the postoperative recurrence of GBM.

Fig. 9 Schematic Illustration of the preparation and therapeutic mechanism of self-assembled nanomicelles (CpG-EXO/TGMa). (A) The preparationof CpG-EXO/TGM. (B) The mechanism of CpG-EXO/TGM traversing BBB. (C) The therapeutic mechanism of CpG-EXO/TGM. Reprinted with permission from ref. 213. Copyright (2023), the American Chemical Society.

Paeoniflorin (Pae) is a water-soluble monoterpene glucoside with potential clinical value for autoimmune and inflammatory disease treatment. However, similar to many other saponins, its bioavailability is low due to glycoprotein efflux and its ease of hydrolysis in the gastrointestinal tract.²¹⁴Glycyrrhiza uralensis Fisch is a commonly used material in TCM given that it can enhance the efficacy and reduce the toxicity of other components. Among the most important properties of GA for pharmaceutical applications are its self-assembly characteristics conferred by its amphiphilic structure. Shen and colleagues designed a spherical particle carrier by self-assembly with GA micelles, and successfully encapsulated paeoniflorin.²¹⁵ This nanoparticle significantly improved the absorption of paeoniflorin in the intestinal tract, enhanced the tissue permeability, conferred its controlled release, and improved its oral bioavailability.

3.1. The mechanism of self-assembly

Herein, we describe the self-assembly of TCM-derived terpenoids, flavonoids, alkaloids, polyphenols, and saponins. These NSMs usually possess functional groups, multiple action sites, hydrophobic side chins, and rigid skeleton, which make it easier for them to form non-covalent bonds and self-assemble. The noncovalent bond interactions between these NSMs mainly include hydrogen bonds, π–π stacking interactions, van der Waals forces, hydrophobic interactions, electrostatic interactions, and coordination interactions. NSMs can directly form SANDDSs through single or multiple noncovalent interactions.²¹⁶

3.2. Hydrogen bonding interactions

Hydrogen bonding is a relatively weak force, which mainly exist between H atoms and electronegative atoms (e.g., O, F, and N).²¹⁷ Hydrogen bonds play an important role in the self-assembly process of natural small molecules. Hydrogen bonding is the main driving force of self-assembly in natural small molecules containing hydroxyl groups, carboxyl groups, amino groups, and amide groups. Terpenoids (such as oleanolic acid, ursolic acid, and betulonic acid) possess structures containing carboxyl groups or hydroxyl groups, and thus hydrogen bond interactions often play the most important role in their assembly process.²¹⁸

3.3. Hydrophobic interactions

Hydrophobic interactions occur when hydrophobic groups (such as polycyclic alkyl skeleton structure containing multiple methyl molecules) aggregate close to each other to avoid water. Some terpenoids contain alkyl side chains and rigid skeletons, and thus hydrophobic interactions are the main driving force for the self-assembly of NSMs in aqueous solution.²¹⁹

3.4. π–π stacking interactions

The π–π stacking interaction is a weak noncovalent interaction, particularly in cases involving aromatic groups with bonded structures.²²⁰ Many natural small molecules contain alkene groups with carbon–carbon double bonds, carbon–oxygen double bonds, or aromatic ring structures, which can easily lead to π–π stacking effects. In this case, π–π stacking interactions are the driving force for the construction of SANDDSs.

Rhein (Rhe) is an anthraquinone compound extracted from the dried roots and rhizomes of rhubarb. Zheng et al. reported a self-assembly of a rhein hydrogel via π–π stacking interactions.²²¹ Bai et al. constructed a carrier-free doxorubicin-Rhe supramolecular, which was prepared by π–π stacking of Rhe and doxorubicin.²²² Lei et al. reported the formation of BBR–Rhe nanoparticles via the direct self-assembly of BBR and Rhe, and the characterization of the Ber–Rhe NPs by UV–Vis spectroscopy, FT-IR spectroscopy, fluorescence spectroscopy indicated that their self-assembly is mediated by the hydrogen bonding or π–π stacking between BBR and Rhe.²²³ Many photosensitizers have aromatic-conjugated structures with C–C double bonds and electron-rich heterocycles, which can co-assemble with NSMs via π–π stacking interactions. Photosensitizer Ce6 consists of a hydrophobic porphyrin ring, and 10-hydroxycamptothecin (HCPT) is an indole alkaloid isolated from the Chinese tree Camptotheca acuminate, which can co-assemble into stable, discrete nanorods through the hydrophobic and π–π interaction between the porphyrin ring of Ce6 with the aromatic ring of HCPT.²²⁴

3.5. Electrostatic interactions

Electrostatic interaction is a non-covalent bond interaction based on the interaction between charges or dipoles, which is influenced by factors such as ion strength, pH level, charge ratio, and concentration. NSMs with charged groups, such as NH₃⁺ and COO⁻ can self-assemble to form nano-drug delivery systems via electrostatic interactions. Thus, BBR as a quaternary ammonium alkaloid can self-assemble into nanoparticles with the carboxyl groups in BAI via electrostatic interactions.⁹³ Aristolochic acid is a component of traditional herbs such as Asarum and Aristolochia, which can be assembled with BBR to form linear supramolecules through electrostatic interactions and π–π stacking interactions.¹⁰⁰

3.6. Coordination interactions

Coordination interactions are medium-strength intermolecular forces that are weaker than covalent interactions and hydrogen bond interactions in strength.²²⁵ Catechol flavonoids or polyphenols with dihydroxyphenyl (catechol) or trihydroxyphenyl (galloyl) structures can coordinate with metal ions to self-assemble and form metal–phenolic networks.

A single type of non-covalent bonding force is often weak and unstable, and thus the self-assembly between small molecules in TCMs is often caused by the combined action of multiple non-covalent bonding forces, thereby forming a stable supramolecular system. Zhang et al. constructed self-assembled Ce6-GA-FA NPs for chemotherapy-photodynamic therapy through the co-assembly of gambogic acid (GA), chlorin e6 (Ce6) and folic acid (FA). Ce6-GA-FA NPs were formed due to the π–π stacking, hydrophobic interactions and electrostatic interactions among the three substances.²²⁶ Yang et al. constructed composite nanoparticles using self-assembling abietic acid (AA) as a carrier to load curcumin. The FITR, UV, and molecular dynamics simulation revealed that hydrogen bonds and hydrophobic interactions are the assembly mechanism of AA loaded curcumin.²²⁷

3.7. The morphology of the self-assembly

NSMs can form a micro-structure feature with various morphologies ranging from nanometers to micrometers through self-assembly in different solvents. Natural small molecules can form fibrous, vesicular, spherical, nanosheets through self-assembly. They may also exhibit phase change behavior by forming nanoparticles, emulsion gels, low-molecular-weight gels, etc., which are influenced by pH, temperature, concentration, and the type of solvent used. Some NSMs can self-assemble into spherical nanoparticles through nanoprecipitation, such as oleanolic acid and ursolic acid, while betulinic acid, glycyrrhetinic acid, and betulic acid self-assembled into nanofibers through the same method.²²⁸ Glycoside baicalin (BA) and wogonoside (WOG) are the main active components in Scutellariae radix, which have a similar molecular skeleton. The two flavonoid glycosides could form different self-assemblies with BBR in aqueous solution, and BA and BBR formed NPs with diameters of 100 nm, whereas WOG and BBR assembled into nanofibers with diameters in the range of 50–100 nm. BA and WOG had similar structures, but their spatial conformation varied, causing them to generate two different self-assembling modes.⁸⁸ In addition to the influence of spatial conception on self-assembly behavior, solvents also have a significant impact on the assembly of supramolecules, such as β-sitosterol can self-assemble into sheet-like, strip-shaped, and fibrous forms in methanol, DMSO, and cyclohexane, respectively.²²⁹

4. Summary and future prospects

The active ingredients extracted from Chinese medicinal herbs for TCM are an important resource for new drug research and development. Due to advances in separation technology, numerous NSMs have been isolated and characterized in detail. However, although many of them have broad spectrum and potent pharmacological activities, they exhibit limited in vivo efficacy due to their poor water solubility, instability, and poor pharmacokinetics, and are often eliminated in new drug screens. The bioactive NSMs of TCM often have multiple hydroxyl or carboxyl structures amenable to hydrogen bond formation and self-assembly with various other molecules. Moreover, NSMs have a unique hydrophobic skeleton that also contributes to their self-assembly. In addition, small molecules involved in assembly often contain carbon-based double bonds (C=O) and olefin double bonds (C=C), even if no aromatic ring produces π–π stacking, which are conducive to π–π interaction and play an important role in molecular assembly. Given the structural heterogeneity of these bioactive molecules, the pathways of self-assembly are diverse. Terpenoids have strong π–π stacking ability and can be assembled with photosensitizers. Flavonoids usually have poor physical and chemical properties for free administration but can be connected to hydrophilic compounds and assembled into a core–shell structure via non-covalent bonds. In these core–shell structures, the inner hydrophobic core can store hydrophobic drugs, such as anti-cancer agents, while the outer hydrophilic shell can protect clinical drugs from destruction. Alkaloids are also common active ingredients of TCM preparations used to construct self-assembled drugs with other natural active ingredients or amino acids to achieve combined treatment or improve bioavailability. The metal phenolic network constructed by polyphenol compounds and metals is another promising system for new drug research and clinical development. By adjusting the types of polyphenols or metal ions, the thickness of MPNs and other physical properties can be controlled and these vehicles can be constructed to include multiple drugs with distinct functions, including anti-cancer agents, photosensitizers, and biological imaging agents. Some saponins have hydrophobic steroidal skeletons and hydrophilic glycosyl side chains that facilitate self-assembly into nanomicelles. In addition, GSs have a steroid structure and can replace cholesterol in the synthesis of liposomes for safer drugs to treat chronic diseases. The construction of appropriate nanodrug delivery systems based on the self-assembly of multiple components from TCM can improve the anti-tumor efficacy, while reducing side effects, thereby expanding the clinical applications of TMC components in modern medicine.

Although NSMs and SANDDSs hold great promise for the treatment of cancer, many theoretical and technical obstacles remain to be overcome. The first is the nature of natural small molecules themselves, such as the low content of natural chemical components in nature, their difficult extraction and separation, poor water solubility leading to poor pharmacokinetics, low bioavailability, and poor stability. For example, many natural components show potential anti-cancer activity in in vitro models, but have poor effect in in vivo models and low success rate in clinical transformation. Accordingly, SANDDSs open a new path for the application of traditional Chinese medicine small molecules, improving their stability, enhancing oral bioavailability, controlled release, and targeted delivery and reducing their toxic side effects. However, there are still many theories to be further studied. The self-assembly of natural small molecules is still in the stage of random and accidental discovery. However, previous self-assembly systems often require a complex preparation process and high cost. In addition, there is a small number of these natural small molecules and their structure type is single, which cannot provide effective clues for the summary of their trends. In addition, a more important point is that the self-assembly between natural small molecules is mostly driven by non-covalent forces. However, due to the weak and dynamic nature of non-covalent forces, it is difficult to determine the relationship between the introduced functional groups and the molecular assembly mode. Therefore, more in-depth studies are needed to clarify the assembly mechanism of molecules in different phase states. Making full use of their self-assembly capability makes it possible to develop new active ingredients of traditional Chinese medicine, promote the clinical transformation of nano-preparations, and improve the clinical application of NSMs.

In addition, we have found that the traditional ‘single chemical’ perspective has limitations for understanding the efficacy of TCM. Rather, the forms and phase states of all the active ingredients as well as the myriad interactions among these molecules influence the efficacy of TCM. Research on self-assembly applications for the active ingredients of TCM may connect TCM theory with modern science and technology and create important avenues for new drug research and development.

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

This work was supported by the Shandong Natural Science Foundation (ZR2022QB075), the Project funded by China Postdoctoral Science Foundation (2022M711983).

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