Recent advances in self-targeting natural product-based nanomedicines

Abstract

Natural products, recognized for their potential in disease prevention and treatment, have been integrated with advanced nano-delivery systems to create natural product-based nanomedicines, offering innovative approaches for various diseases. Natural products derived from traditional Chinese medicine have their own targeting effect and remarkable therapeutic effect on many diseases, but there are some shortcomings such as poor physical and chemical properties. The construction of nanomedicines using the active ingredients of natural products has become a key step in the modernization research process, which could be used to make up for the defects of natural products such as low solubility, large dosage, poor bioavailability and poor targeting. Nanotechnology enhances the safety, selectivity, and efficacy of natural products, positioning natural product-based nanomedicines as promising candidates in medicine. This review outlines the current status of development, the application in different diseases, and safety evaluation of natural product-based nanomedicines, providing essential insights for further exploration of the synergy between natural products and nano-delivery systems in disease treatment.

Graphical Abstract

Introduction

Natural products are naturally occurring substances from animals, plants, and microorganisms that possess significant biological activity and therapeutic potential, frequently employed in the field of pharmaceuticals [1, 2]. Traditional Chinese medicine (TCM), as a natural product, occupied an outstanding role in the field of medicine due to the presence of a wide range of biologically active compounds such as alkaloids, terpenoids, flavonoids, etc. [3,4,5,6,7,8,9,10,11]. The active components in TCM derived from natural products exhibit self-targeting properties, which greatly reduces side effects. In addition, their ability to stimulate both specific and non-specific immune responses leads to enhancement of overall immunity [12,13,14]. Therefore, natural products have unique advantages in ensuring safety, reducing side effects, integrative modulation, enhancing immunity, and improving efficacy [15, 16]. Despite their potential, the unfavorable physicochemical properties of these natural products such as poor dissolution, limited bioavailability, short half-lives, and instability in biological environments due to their non-polar characteristics, have hindered their clinical application [17,18,19]. Thus, integrating advanced scientific and technological methods is essential for modernizing natural products.

Nanotechnology applied in medicine has a long-established track record of application [20]. Owing to the distinctive properties of nanosubstance at the nanoscale, nanomedicine has emerged as a formidable tool for creating innovative pharmaceutical formulations, encompassing nanoparticles, nano emulsions, nanoparticles, microcapsules, liposomes, nanocontainers, etc. [21]. The strengths of nano formulations are primarily to enhance the therapeutic effects, improve bioavailability, sustain and control release, target effects, reduce toxicity and enrich drug dosage forms [22]. Consequently, the integration of natural products with nano-delivery systems enhances solubility and bioavailability, extends half-life, improves targeting, reduces gastrointestinal irritation, and minimizes interindividual variability in drug administration [23, 24].

Recently, with the rapid development of natural products and nanotechnology, in order to solve their respective problems, the two have carried out reasonable cooperation to obtain better therapeutic effects, which has become the focus of attention [25]. As a new type of pharmaceutical dosage form, natural product-based nanomedicines have been studied in the aspects of assembly technology, drug delivery system, and disease treatment [17, 26,27,28,29]. Nonetheless, a systematic framework for the implementation of natural product-based nanomedicines against various diseases is currently absent. Hence, this paper aims to investigate the potential of pharmaceutical preparations utilizing natural product-based nanomedicines for disease treatment. It will address the development status of these nanomedicines, their targeted applications in diverse diseases, and safety assessments. It is hoped that it could provide more possibilities for the development of pharmaceutical preparations based on natural products and the subsequent clinical practical application.

Development status of natural product-based nanomedicines

The application of nanotechnology in natural product manifests chiefly in drug delivery system constituted of natural product [12] or loaded natural product [30]. The results showed that there are many kinds of effective components of natural product, unique structure, and self-assembly ability to form a nano drug delivery system to achieve carrier-free and high stability drug delivery [31]. Self-assembly of the active components of natural product means that the molecules could spontaneously form nanostructures in different solvents through non-covalent bond forces (hydrogen bonding, electrostatic interactions, van der Waals force, π–π stacking, hydrophobic interaction and coordination interaction, etc.) under equilibrium conditions [5, 32]. Because of the different structure of the active ingredients of different natural product, the mechanism of self-assembly behavior was different [5, 33]. The assembly mechanism and disease applications of natural product-based nanomedicines were displayed in Fig. 1. The complex structure of saccharide was rich in a large number of hydrophilic groups, so it could be combined with other structural units through hydrophobic or hydrogen bonding, showing self-assembly potential [34]. Triterpenoids have rigid skeleton, multi-chiral center and amphiphilic properties, and are easy to fold in various forms in different media for self-assembly [35]. Flavonoids contain phenolic hydroxyl groups, aromatic rings, hydrophobic groups and functional groups that can coordinate with metals, so that flavonoids can form self-assembled structures [36]. Alkaloids may contain hydrophilic groups and hydrophobic groups as well as rigid scaffolds and multi-chiral centers, which can either self-assemble through hydrophobic interaction and hydrogen bonding in water or fold into self-assembled nanoparticles in various forms in different media [5, 6]. Aglycones of glycosides are usually hydrophobic, while glycogroups are hydrophilic, and this amphiphilicity allows them to form nanostructures in aqueous solutions through hydrogen bonding and hydrophobic self-assembly [37]. Polyphenols with the catechol or pyrogallol structures promote self-assembly primarily through hydrophobic interactions, electrostatic interactions, π–π tacking, hydrogen bonding, boronate bonding, and metal coordination [5, 6]. The self-assembled carrier-free nano delivery system of natural product combines the characteristics of prodrug strategy, molecular self-assembly and nanotechnology, and has the unique advantages of simple preparation process, high drug loading, no need for carrier materials and low toxicity [38]. Moreover, the drug delivery system incorporating active constituents of natural product utilizes target-modified nanocarriers to transport insoluble ingredients into the body. Angelica sinensis polysaccharide (ASP) exhibits a strong affinity towards the asialoglycoprotein receptor (ASGP-R), a well-established target receptor in liver cells. Therefore, ASP-modified hypoxia-responsive polymeric micellar carriers allowed efficient and precise delivery of insoluble curcumin [39] to the liver for the treatment of HCC [39, 40]. Recently, the innovative application of biomimetic nano approaches in the field of natural product had become a hotspot, which not only improves the safety and effectiveness of natural product, but also promoted the modernization and internationalization of natural product.

Fig. 1

Assembly mechanisms and disease applications of natural product-based nanomedicines

The introduction of doxorubicin (DOX) hydrochloride liposomes in 1995 has led to the availability of numerous nano preparations in the market for clinical use [41]. The primary uses in illnesses are cancer [42], neurological disorders [43], and hematological disorders [44]. The use of Paclitaxel, a diterpene alkaloid that comes from the bark of Picea rubra, is common for treating breast cancer, ovarian cancer, lung cancer, and other cancers [45,46,47,48]. The currently marketed paclitaxel nano-formulations included liposomes, albumin nanoparticles and polymeric micelles. Taxol®, which was marketed as a paclitaxel injection in 1992, was the initial formulation, but the polyoxyethylene castor oil in its formulation has the potential for allergic reaction [49]. Taxol®'s long-term dominance of the market was ended by Abraxane®, which became the top-selling cancer drug of all time in the US in 2005 [50]. Abraxane® is the paclitaxel nanoparticle that is bound to albumin and focuses on the tumor site after intravenous injection, resulting in enhanced therapeutic effects and fewer side effects worldwide [51]. Lipusu^®, a liposome injection containing paclitaxel, was granted approval by the SFDA in 2003 and is widely available for treating ovarian and non-small-cell lung cancers via intravenously [52]. In addition, there are currently clinical trials underway for liposomal forms of paclitaxel, LEP-ETU^®, and Endo TAG^®-1 [53]. Efficacy and toxicity can be improved by using polymeric micelles in the formulation of paclitaxel, as demonstrated by the development of Genexol^®-PM by Samyang in Korea [54,55,56]. Despite extensive basic research, clinical application is still centered around liposomes and polymer micelles. Successful implementation of nanomedicines that have multifunctionality, targeting, and environmental sensitivity has not been achieved yet [57]. Not to mention the fact that nano-formulations of natural product related to natural products have been few employed in the clinical, the development and utilisation of active ingredients of natural product is inevitably still a long journey ahead of us.

Application of natural product-based nanomedicines in different diseases

Natural product-based nanomedicines are effective in improving the solubility of free compounds, improving biocompatibility, and reducing off-target toxicity [58]. In addition, it monitors the agent's distribution inside the body and has a potentiating and toxic-reducing effect [59, 60]. The therapeutic role of natural product-based nanomedicines in diseases of various body parts has been demonstrated through research since it was developed (Table S1). Targeting diseases or organs with natural product-based nanomedicines enables drug aggregation to be enhanced and therapeutic effects to be achieved [61]. The primary method of targeting involves the combination of active ingredients with receptors at the disease site or the introduction of relevant ligands [62, 63]. Furthermore, natural product-based nanomedicines are capable of overcoming systemic, microenvironmental and cellular biological barriers, including the BBB, to prevent and treat brain diseases [64]. Finally, the enhanced permeability and retention (EPR) effect assists natural product-based nanomedicines in reaching the disease site for therapeutic purposes [65, 66]. The physical and chemical deficiencies in the active ingredients are addressed by natural product-based nanomedicines, which enhances their pharmacological and pharmacodynamic effects [67, 68]. Consequently, there are more possibilities for the clinical treatment of diseases.

Self-targeting refers to the intrinsic targeting ability of a drug to specifically target cells or organs without additional targeting molecules [69]. Self-targeting natural product-based nanomedicines is the combination between natural products with intrinsic targeting ability and nanotechnology [70]. Just as the theory of “guiding action” in TCM, drugs are selective to the body, which is based on the theory of viscera and meridians in TCM and has experienced long-term clinical practice, and has important guiding significance for enhancing the accuracy of drug use. The theory of "meridian tropism of medicinal herbs" in TCM aims to automatically locate and treat the affected organs and meridians [71]. When these TCM therapies have a significant impact on specific meridians, they are referred to as their "guiding role" [72]. The meridian-tropism in TCM theory is consistent with the concept of self-targeting of natural products [73, 74]. Unlike some targeting ligands (such as hyaluronic acid, folic acid (FA), mannose) that have almost no therapeutic effect, some natural products have both targeting and therapeutic effects [3, 75]. Enhanced targeting capabilities, reduced side effects and improved efficacy are among the notable advantages it presents [76, 77]. The targeting mechanism of natural product-based nanomedicines relies on the unique properties of active compounds in each TCM, alongside the characteristics of the disease site. These nanomedicines can effectively localize at the target site via passive targeting (e.g., EPR effect) and active targeting mechanisms. Active targeting leverages the inherent targeting properties of TCM active ingredients [78] and enhances delivery through ligands that specifically bind to inflammation or tumors, ensuring precise and effective treatment. This approach addresses the limitations of traditional therapies, improving selectivity, delivery efficiency, bioavailability, and mitigating multi-drug resistance. Self-targeting nanomedicine can be customized for individual patients, fostering the advancement of personalized nanomedicine [79, 80]. Figure 2 illustrated various ways in which natural product-based nanomedicines can enter the disease site to perform its therapeutic function. The selective targeting of specific organ tissues was significant for the advancing of natural product-based nanomedicines systems.

Fig. 2

Reproduced with permission from ref. [17]. Copyright © Controlled Release Society 2021

The primary targeting modality of natural product-based nanomedicines for the therapy of disorders. a EPR effect in tumor tissue. b Receptor-ligand based proactive targeting. c Brain targeting by crossing the BBB.

Natural product-based nanomedicines against liver disease

According to the theory of TCM, the liver is considered as the "organ of general" due to its paramount importance. Given that liver disease ranks among the most prevalent ailments in humans, addressing liver diseases and safeguarding hepatic health have become pressing concerns [81]. Numerous studies have demonstrated that various active compounds in natural products have significant potential to ameliorate liver injury, restore optimal liver function, and treat diseases such as hepatic tumors [82]. In addition, certain active ingredients in natural products have inherent self-targeting properties that enable them to effectively exert therapeutic effects on liver diseases. For instance, glycyrrhizic acid (GL) and GA exhibit a liver-targeting function due to the presence of specific GL/GA-R receptors in the liver that facilitate their binding [83]. Studies have demonstrated that the integration of active components with nano-delivery systems yields highly targeted drug delivery to the liver and synergistic therapeutic effects for liver ailments (Fig. 3).

Fig. 3

Copyright 2017 Lv et al. b The synthetic route of AAAF@Cur and its pathway through ASGP-R targeted delivery of its to tumor sites to play a therapeutic role, where the bar graph illustrates the cell viability of HepG2 cells 24 h AAAF@Cur micellar and free Cur under hypoxic and normoxic conditions [40]. Copyright 2021 The Author(s). c The synthetic route of Gal-MPL/Lut and its targeted delivery to tumor sites through ASGPR are shown as oil red O staining (top) and Bodipy staining (bottom) of HepG2 cells [85], Copyright 2023 Elsevier B.V. d The synthetic route of ECH@AMPG and its passage through the ubiquitin protein ligase E3 component N-recognin 5 (UBR5) targeted delivery to the tumor site to play a therapeutic role, and in vivo small animal imaging showed the survival of HepG2 cells after different drug interventions [86]. Copyright the Author(s) 2022. Several elements in the image were obtained from https://biogdp.com [87]

Selected results of natural product-based nanomedicines against liver disease. a The synthesis route of MSN-GA-CUR and its therapeutic effect through the targeted delivery of GA receptor to the tumor site, among which CLSM image shows HepG2 cells incubated with 100 μg/mL C-6-MSN-GA (I), C-6- MSN (II) after 30 min [84].

GA is a terpenoid active ingredient with natural hepatoprotective properties and demonstrating remarkable anticancer activity [83]. The rationale behind the hepatic targeting of GA lies in its receptors being expressed on the surface of mammalian hepatocytes, with its presence on liver tumors being 1.5-5 times higher than that in normal tissues, thereby facilitating targeting of GA towards liver tumors. Numerous nano-delivery systems for HCC treatment have been developed, leveraging the liver targeting ability and anti-tumor effects of GA [88]. Taking full advantage of the ability of GA to target liver tumors, the nanocarriers were designed and prepared together with Cyclodextrin [89] and Prussian blue (Pu) to deliver the anti-HCC drug DOX. The prepared DOX/GCDPu NPs showed improved drug bioavailability, reduced cardiac and renal toxicity, enhanced liver targeting and demonstrated excellent anti-tumor effect [90].

The advantage of GA ligands was that they compensated for the lack of specificity of the receptor and rarely induced an immune response. The copolymer micelles (GA-PEG-PHIS -PLGA, GA-PPP) were formed from GA and aromatics by grafting of active terminal groups. The AGP/GA-PPP nanoparticles loaded with anticancer drug andrographolide (AGP) enable bifunction drug delivery to enhance anti-tumor activity by exploiting the liver tumor targeting and pH-triggered drug release mechanism of GA [91]. In order to better play the role of adriamycin in the treatment of HCC, GA-cs-pei-hba-dox with liver targeting effect using GL receptor was designed. With its pH-sensitive response and receptor-mediated targeting, it not only greatly improved the delivery efficiency, but also exhibited a stronger inhibitory effect on HCC cells [92]. Additionally, GA- modified D-a-tocopherol PEG 1000 succinate polymeric micelles were designed for targeted delivery of etoposide to HCC cells. Studies confirmed that the micelle showed a high aggregation effect at the liver tumor site, indicating its good tumor targeting and anti-tumor effect [93]. A safe and efficient new nanocarrier GO was designed to synthesize GPND/siRNA with GA, PEG and polyamide-amine dendrimer, which overcame the shortcomings of siRNA itself and enabled the drug to successfully target liver tissue and effectively inhibited the growth of tumor tissue [94, 95]. Daphnetin, is an effective component of coumarin, could induce apoptosis of HCC cells and inhibit tumor growth, but its application was restricted due to poor solubility. Taking advantage of the targeting property of GA and the EPR effect of nanoparticles on tumors, a nano system GPP/PP-DAP with both active and passive targeting effects was designed to deliver reserpine to liver tumors to enhance the therapeutic effect [96]. CUR was the active ingredient of polyphenols. It had anti-inflammatory, anti-oxidative, anti-angiogenic activities and anti-tumor effects, but with poor water solubility and low bioavailability. The MSN-GA-CUR prepared by CUR and GA had liver targeting and a higher drug loading capacity, so it possessed a higher tumor drug uptake to enhance tumor inhibition effect [84]. The MSN-GA-CUR synthesis route was shown in Fig. 3a. The drug delivery system of pure natural product-based nanomedicines as carrier is directly co-assembled by small molecular natural compounds through non-covalent interaction. Oleanolic acid (OA) and GA co-assembled nanoparticles had good stability, high drug loading and synergistic anti-tumor effect. After drug loading, the anti-tumor effect was better, and the side effects of chemotherapy and additional toxicity caused by nanocarriers were reduced [97].

Polysaccharides are often used as targeted drug carriers. Angelica polysaccharide (ASP) is a plant polysaccharide with good biocompatibility and intrinsic liver targeting ability. Amphiphilic conjugate (ASP-DOCA) is prepared by modifying hydrophobic groups (deoxycholic acid), and the self-assembled nanoparticles can be targeted to deliver the therapeutic drug DOX for liver cancer. It showed better antitumor activity [98]. ASP was a polysaccharide component with antitumor activity but poor water solubility. It had a high affinity for salivary glycoprotein receptor (ASGPR), the most well-known target receptor in hepatocytes, therefore, based on the natural liver targeting ability of ASPs, a polymeric micelle AAAF@Cur co-prepared with CUR was developed (Fig. 3b). The micelles owned considerable biocompatibility and specific liver targeting, and could achieve responsive drug release in the tumor microenvironment to play an anti-tumor therapeutic role [40]. Lignans possess lipid intervention potential but have solubility and release problems. Gal-MPL/Lut nanoparticles were spherical, small and liver-targeted. In HepG2 cells, they facilitated Lut uptake and regulated lipid metabolism [85]. The specific synthesis route was demonstrated in Fig. 3c. Echinacoside (ECH), a phenylpropanoid component, existed potent anti-proliferative and pro-apoptotic activities against a variety of tumors, but had poor absorption and low bioavailability when administered orally. Based on the advantage that ECH could target and reduce the expression of the UBR5 oncogene expressed in liver cancer, an MSN drug delivery system (ECH@AMPG) was synthesized by coupling galactose and poly (ethylene glycol) diethylene glycol ether (PEGDE) (Fig. 3d). This enhanced the anti-liver tumor effect of the nanoparticles. Tumor-targeting nanoparticles had good biosafety and significantly reduced glycolysis and promote apoptosis of HCC cells [86].

Triptolide (TP) categorized as a diterpenoid with significant anti-autoimmune and anti-tumor effects. However, TP presented disadvantages such as toxic reactions, low solubility, low bioavailability, and adverse reactions. Nanoliposomes improved the solubility and stability of TP and enhanced the therapeutic effect on tumors, but had no specific targeting ability to tumors [99]. Considering the overexpression of transferrin receptor (TfR) in human hepatoma cell line HepG2, the targeting molecule transferrin (TF) was introduced into the preparation of nanoliposomes. Experiments revealed that TF-TP@LIP and TF-DBC NPs (Tf-decorated, dihydroartemisinin (DHA), L-buthionine-sulfoximine, and CellROX-loaded liposomal nanoparticles) significantly enhanced tumor targeting and anti-tumor effects of TP and DHA [100, 101].

Matrine proteolytic targeting chimera (PROTAC) LST-4 had better antitumor activity than matrine. By self-assembly of LST-4 encapsulating Zinc (II) Phthalocyanine, LST-4@ZnPc NPs produced could be enriched in lysosomes through EPR effect, with low pH triggering drug release properties, combined with the application of chemotherapy and phototherapy, and finally effectively killed tumor cells [102].

Rhein was self-assembled through hydrogen bonding, π–π stacking interaction and hydrophobic interaction, and combined with chemotherapy drug DOX to form a highly efficient nanomaterial (Rhein-DOX nanogel) that could release drugs continuously. It had been proved that the nano-gel could improve the bioavailability of rhein, reduce DOX toxicity, target mitochondria, induce ROS production and promote cell apoptosis, and significantly improve the synergistic anti-liver cancer efficacy, and was a low-toxicity and long-term anti-liver cancer drug [103].

The lipid conjugation of camptothecin (CPT) enabled nano assembly in aqueous solutions without excipients. Nano assemblies composed of CPT conjugated with linoleic acid and sorafenib exhibit stability and sustained release of payload. The combination of nanoparticles inhibited the growth of HCC continuously, which had the hope to overcome the drug resistance of liver cancer [104].

Natural product-based nanomedicines against brain disease

The brain is an essential organ of the human body which is called “Qi Heng” in the theory of TCM and it is the House of the First Spirit, and the Source of the Divine Mechanism. Lesions of brain tissue can lead to the development of many diseases, among which glioma lesions showed a low degree of differentiation, poor prognosis and were prone to recurring episodes, posing a serious threat to the safety of human life. A more detailed understanding of brain mechanisms, research into the development of new drugs and finding suitable brain delivery routes for the palliative treatment of brain lesions may be a new trend in development [105, 106]. Natural products with their multiple targets and synergistic effects are often used in the treatment of brain diseases [107]. Nevertheless, the BBB, a natural barrier system that exists between the blood system and the brain cells and cerebrospinal fluid, provides effective protection for brain tissues from harmful substances, but also prevents many drugs from passing through the BBB [108,109,110]. Whether this problem can be effectively addressed is crucial to research and development of brain therapeutics (Fig. 4).

Fig. 4

Copyright 2023 Published by Elsevier Masson SAS. b Synthesis pathway of L-D-I/NPs, where imaging graph showed comparison of fluorescence intensity in GBM in situ loaded mice at different time points after intravenous injection of L-D-I/NPs and other drugs [112]. 2023 Wiley–VCH GmbH. c Synthesis pathway of DiR-MM-BA-LP, where the imaging plots show the fluorescence intensity of rats after intravenous injection of DiRBA-LP and DiR-MM-BA-LP, respectively [113]. Copyright 2022 Published by Elsevier Inc. d Synthesis pathway of ApoE-Res/Sal-Lips, where imaging plots show comparative in vivo real-time imaging after administration of different preparations to APP/PS-1 mice [114]. Copyright 2023 Informa UK Limited, trading as Taylor & Francis Group

Several results of natural product-based nanomedicines against brain disease. a Synthesis pathway of BO-BA-LP and drug treatment using the BBB-promoting osmotic effect of (-)-Borneol (BO), in which bar graphs show the BA concentration of BA- LP and BO-BA-LP in mouse brain tissue [111].

The flavonoid ingredient resveratrol and the glycoside compound salidroside (Sal) have an impact on the trajectory of biomarkers of AD. However, they suffer from poor specificity, low solubility and insufficient BBB permeability [115]. ApoE penetrated the BBB and enters the central nervous system because it targeted both lipoprotein receptor-associated protein 1 (LRP1) and LDLR receptors, which were highly expressed in the BBB. Therefore, using ApoE as a targeting ligand to design the nano-liposome delivery system could make Res and Sal better absorbed with stronger ability to penetrate the BBB and higher transport efficiency (Fig. 4d), which could reduce the learning and memory disorders, improve the brain function and alleviate the symptoms of AD [114].

Both tanshinone IIA (TanIIA) and GL induced apoptosis in GBM cells. However, they had the disadvantages of low solubility and excessive metabolism in vivo or hemolysis at certain doses. Because TfR was highly expressed in BBB/BBTB and GBM cells, the preparation of nanoparticles enriched with TfR-expressing extracellular vesicles (EXOs) could enhance drug penetration to the BBB and brain targeting, prolong blood circulation time and enhance anti-tumor effect. This is a biomimetic nanomedical drug delivery platform based on endogenous exosomes, in which endogenous serum exosomes are coated with pure drug nanomicelles [116].

Emodin [117], an anthraquinone component, had anti-inflammatory, anti-viral and anti-tumor effects [62] and could treat most brain diseases, but it rarely reached the brain through intravenous injection [118]. Considering the brain-targeting effect of cyclic Arg-Gly-Asp (cRGD) peptide ligands, PEG and cRGD were selected for modification in the preparation of liposomes for EMO delivery. The results showed that the nanoliposomes could target to the brain without disrupting the BBB and down-regulate the expression of AQP4 to improve the symptoms of ischemic stroke [119].

The alkaloid component Rhynchophylline (RIN) exerted neuroprotective effects on AD and cerebral ischemia through various mechanisms such as anti-oxidation, anti-inflammation and regulation of neurotransmitters [120]. However, poor water solubility, low bioavailability and poor penetration of the RIN limited its practical application. Tween 80-coated nanoparticles could cross the BBB through the lipoprotein receptor-related proteins (LRPs)-mediated cytotransmission and thus the nanoparticles could be loaded with drugs to cross the BBB and achieve neuroprotection for the treatment of AD [121].

Cannabidiol (CBD) was a phenolic compound, which itself was non-addictive, low-toxicity and possessed anti-inflammatory, anti-stress, anti-anxiety, anti-epileptic and neuroprotective effects. Nevertheless, it suffered from the drawbacks of low water solubility, poor bioavailability and slow targeting to the brain. Macrophage membranes could pass the BBB and liposomes also had a high affinity for the BBB [122]. Hence, it was experimentally demonstrated that the CBD-loaded biomimetic macrophage membrane vesicles liposomes could successfully cross the BBB with better drug loading and drug circulation time and had a therapeutic effect on post-traumatic stress disorder (PTSD) [123].

The ketone constituent muscone altered the permeability of the BBB and the diterpene compound docetaxel (DTX) had a therapeutic effect on a variety of cancers, especially gliomas. The mouse monoclonal antibody RI7217 had high affinity and selectivity for TfR overexpressed in brain cells (hCMEC/D3) and glioma cells. The liposomes synthesized according to this design could improve the permeability of BBB and target drug delivery into the brain for the treatment of glioma with good therapeutic effect [124]. The design of muscone and DTX as nanoliposomes also correlated with the overexpression of TfR in both brain endothelial cells and glioma cells and muscone could increases the permeability of the BBB. Therefore, dual-targeted liposomes with the ability to cross the BBB were prepared for targeted therapy of gliomas [125, 126].

Borneol (BO) categorized as a monoterpene composition was commonly used as a permeation enhancer to deliver drugs across the BBB. When modified with different types of nanocarriers (e.g. NPs, nano emulsions, liposomes, etc.), BO increased the solubility of the drug, improved the cellular uptake, reduced the toxicity of the nanocarriers, decreased the toxicity to the cells and organs and enhanced the cerebral targeting of the drug delivery system that improved the power of anti-tumors. Its main mechanism of action was to regulate the proteins responsible for drug transport from the cell membrane and inhibit their overexpression, including the ABC transporter superfamily MRP1/ABCC1 and P-gp/ABCB1 [127]. Baicalin (BA) used to treat cerebral ischemia–reperfusion injury but hardly crossed the BBB. Based on the property of BO to promote drug entry into the brain, borneol-baicalin liposomes (BO-BA-LP) were prepared to improve the ability of BA to penetrate the cell membrane in vitro, which is demonstrated in Fig. 4a [111]. BA liposomes (BA-LP) were prepared by extrusion method because of the modification of macrophage membranes (MM-BA-LP), and baicalin brain targeting was enhanced (Fig. 4c) [113]. To increase the distribution of itraconazole in the brain, a novel brain-targeted delivery system based on BSA was designed. Experiments demonstrated that the nano-delivery system actually helped the drug to cross the BBB and target the brain [128].

Both flavonoid Icariin and quinone TanIIA have neuroprotective effects on AD. However, they both presented drawbacks such as poor aqueous solubility and low bioavailability when administered orally. Liposomes targeted into the brain, low-density LRP1 was overexpressed on the BBB and Angiopep-2 could highly bind to LRP1. Based on the above, nanoliposomes were selected for the preparation and synthesis and experimentally verified that the nano delivery system could successfully cross the BBB, with brain-targeting properties and play a promising therapeutic role in AD [129]. In addition, the antimalarial drug dihydroartemisinin and the photosensitizer indocyanine green (ICG) were loaded onto lactoferrin (LF) for self-assembly into L-D-I/NPs. which also bound to LRP1 could cross the BBB and selectively target glioblastomas to promote intracerebral aggregation of DHA (Fig. 4b) [112].

Nanocarriers containing curcumin were coated with modified red blood cell membranes to treat Alzheimer's disease (AD). The nanoparticle could be recognized by receptors on the blood–brain barrier (BBB), delivering drugs to the brain to delay the progression of AD [130].

Dihydroartemisinin, a sesquiterpene constituent, displayed significant inhibitory effects on glioblastoma, but its poor water solubility and short residence time in the blood prevented it from fully exerting its efficacy. Based on the property that lactoferrin was able to interact with low-density LRP1 to cross the BBB, biomimetic nanoplatform of DHA and lactoferrin was designed and synthesized [125, 131].

Vinpocetine, a compound of the indole alkaloid vincamine, had been widely used in cerebrovascular diseases. A self-enhancing brain-targeting nucleic acid delivery lipid nanoparticle (VIP) was developed based on this cyclic tertiary amine compound, which could effectively break through the BBB, has good safety and has a synergistic effect on the treatment of brain diseases [132].

Natural product-based nanomedicines against heart disease

The heart as one of the most essential organs of the human body serves as the "official organ of the ruler". Heart disease, as the most dangerous disease to human health, is even life-threatening in severe cases [133]. The general treatment means were surgery and medication [134]. With the progress of science and technology, the research of natural product-based nanomedicines in heart disease is gradually increasing, which can improve the shortcomings of poor solubility and poor targeting of anti-heart disease drugs [135] (Fig. 5).

Fig. 5

Copyright 2022 The Authors. b chitosan/HEC/puerarin/MSNs (CHP@Si) synthetic pathway and mechanism of action [137]. Copyright The Author(s) 2023. c CUR-Bio PLGA NPs synthesis pathway and mechanism of effect [138]. Copyright 2021 by the authors

Several results of natural product-based nanomedicines against heart disease. a Synthesis pathway and mechanism of action of MSN-NGR1-CD11b antibody NPs [136].

Notoginsenoside R1 (NGR1), an effective saponin, could stop bleeding and resolve blood stasis, reduce swelling and relieve pain and was often used in the treatment of myocardial infarction (MI). In the early stages of MI, the infarct site was characterized by the aggregation of CD11b-expressing monocytes and neutrophils and thus the introduction of CD11b antibodies might enable the targeting of ingredients with good therapeutic effects into the lesion site. The strategy of loading CD11b antibody into NGR1 via MSN (MSN-NGR1-CD11b antibody NPs) allowed for the non-invasive and precisely targeted delivery of NGR1 to the heart, improving cardiac function and angiogenesis, decreasing apoptosis and more (Fig. 5a) [136].

MI was accompanied by early inflammatory response and capillary obstruction and rupture, whereas puerarin was a flavonoid ingredient with anti-inflammatory and vasodilatory effects. It was demonstrated that chitosan/HEC/puerarin/MSNs (CHP@Si) composite hydrogel could most effectively deliver puerarin to the lesion site at a puerarin concentration of 5 mg/mL, thereby inhibiting the expression of pro-inflammatory genes. Silica ions released from the hydrogel also synergized with geraniol to enhance the viability of HUVECs cells, promote their migration and increase the expression of angiogenic genes. This injectable hydrogel holds promise for the clinical treatment of MI (Fig. 5b) [137].

Phenolic components were known to have antioxidant, vascular wall strengthening, lipid-lowering and atherosclerosis preventive effects. CUR, a member of the polyphenol family with multiple activities and cardiovascular protection, was studied in both Friedreich's ataxia (FRDA) and atherosclerosis [139]. The main etiology of FRDA was abnormal iron metabolism, mitochondrial dysfunction and the resulting oxidative damage. The disease was caused by mutations in frataxin, and reduced expression of frataxin affects the biogenesis of iron-sulfur clusters. Fibroin is a kind of natural protein, which is more prominent in drug release when it is used as a carrier. Synthesis of slow-release nanoparticles (NPs) by doping polycurcumin into silk fibroin [140] improved its water solubility and permeability, allowing it to exert better iron binding and antioxidant capacity. In this way, CUR@SF NPs not only scavenged iron from the heart and alleviated oxidative stress, but also promoted the biogenesis of iron-sulfur clusters, which compensated for the reduced frataxin expression and enhanced the morphology and function of mitochondria [141]. Atherosclerosis (cholesterol-rich arterial plaques) triggered heart disease, so anti-atherosclerotic drugs might be effective in preventing heart disease to a certain extent and CUR possessed good anti-inflammatory and antioxidant properties but was limited by its low aqueous solubility. It was demonstrated that CUR-Bio PLGA NPs (a combination of CUR and bioperine nanoparticles), on the one hand, solubilized and synergized CUR and on the other hand, targeting the atherosclerotic site could down-regulate the expression of mRNA of genes related to the inflammatory pathway, which showed great potential in anti-atherosclerotic therapy (Fig. 5c) [138].

Natural product-based nanomedicines against spleen and other lymphoid organs disease

The spleen as the largest lymphatic organ in the human body, functions in TCM to transport water and grain essence to the whole body [142]. Lymphoid organs are lymphoid organs with lymphoid tissue as their main constituent [143]. They are called immune organs because of the immune function they perform in the body, including the thymus, spleen and tonsils [144]. Problems in the immune system will lead to a series of serious consequences [145]. Currently, some studies have shown that some natural product-based nanomedicines could target the lymphoid organs, which might offer some references for the treatment of immune disorders.

Bee venom peptides exhibited excellent antitumour and immunomodulatory properties but their application was limited due to their haemolytic side effects. α-melittin-lipid NPs were cholesteryl oleate (CO) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) α-melittin-lipid NPs, which were synthesized using vertexing and ultrasound techniques with melittin peptides. α-melittin-lipid NPs activated macrophages and DCs in the LNs and induced innate immune cell infiltration, which exerted primary and distal tumor suppressive effects. Mice treated with α-melittin-lipid NPs showed a 95% and 92% reduction in primary and distal tumor volume, respectively. The α-melittin- lipid NPs maintained the killing effect of melittin on tumor cells and induced in situ release of whole tumor antigens, showing their great potential as LN-targeted whole-cell nano vaccines [146].

AGP had excellent activity but low water solubility, short half-life and low permeability, The AGP-loaded solid lipid nanoparticles (AND-SLN) could improve the efficacy and enhance the bioavailability and specificity of the drug in spleen and thymus [147].

Twenty-four hours after tail vein injection, nanoparticles Cy5-NP(Gla)-5 k loaded with glabridin (Gla) co-localized with peripheral macrophages in the penumbra due to splenic targeting [148]. Furthermore, titanium dioxide nanoparticles were used as photosensitizers for therapeutic applications in tumors and other diseases, but significantly induced oxidative stress in the spleen of rats, leading to a decrease in serum immunoglobulin levels. Quercetin (Qu) as a flavonoid constituent had potent antioxidant properties. It was shown that Qu (50 mg/kg/d) down-regulated the expression of apoptotic markers and pro-inflammatory factors and alleviated the morphological alterations caused by titanium dioxide nanoparticles (300 mg/kg/d) in rat spleen [149].

Natural product-based nanomedicines against lung disease

TCM refers to the lungs as a "delicate organ" (delicate and susceptible to external invasion), which is mainly responsible for respiration, i.e., the operation of gases throughout the body. Common lung diseases include pneumonia, tuberculosis and lung cancer, etc. [150, 151]. The development of natural product-based nanomedicines will, to a certain extent, provide a more powerful tool to change the traditional way of treating lung diseases and to treat lung diseases efficiently and accurately (Fig. 6).

Fig. 6

Copyright XXXX American Chemical Society. b Synthesis route of MNPs@Cur and different nanoparticle biodistribution fluorescence [153]. Copyright 2022 Elsevier B.V

Two investigations of nanomedicines based on natural products against lung diseases. a The synthetic route of CCM@ SBA-15/PDA/Ag and bar graphs demonstrating the cytotoxicity of CCM@ SBA-15/PDA/Ag and other drugs incubated in A549/TAX cells [152].

The development of lung diseases such as acute lung injury (ALI), pneumonia and asthma were associated with the emergence of an inflammatory response. Qu, a well-known anti-inflammatory and antioxidant agent, had great potential in the treatment of ALI. The main pathogenesis of ALI was inflammation and oxidative stress. Qu is stabilized by hydrogen bonding to obtain a “co-constructed” water-soluble nanogel. Qu-arginine nanogel (Qu-Nanogel) with a particle size of less than 100 nm improved the solubility and bioavailability of Qu. Together with the ultrasonic aerosol inhalation delivery method, it allowed the drug to be precisely targeted into the lungs, thus playing a role in attenuating oxidative stress injury and down-regulating the expression of inflammatory cytokine mRNAs and proteins in ALI rats [154].

Pneumonia pathogenesis was also mainly due to uncontrolled inflammation in lung tissues and blocking the cytokine storm was the key to treatment. Macrophage membrane-encapsulated reactive oxygen species (ROS)-responsive Platycodon grandiflorum polysaccharides (PGP) biomimetic nanoparticles (PNPs)-derived drug-delivery platforms (MNPs) were constructed based on TCM theory of drug-induction and macrophages' intrinsic affinity for inflammatory sites (Fig. 6b). It was demonstrated that MNPs@Cur with the addition of CUR, an anti-inflammatory agent of TCM, significantly attenuated inflammation in mice with ALI by inhibiting the production of pro-inflammatory factors and the infiltration of inflammatory cells. In addition, the strong lung-targeting ability of PNPs compared with other polysaccharide vectors also validated the theory of channel tropism [153].

Asthma was a class of chronic inflammatory diseases. Baicalein (BA), as a cytoprotective and anti-inflammatory flavonoid, might have anti-asthmatic potential. Treatment of asthma model mice with BA encapsulated and encapsulated in chitosan nanoparticles resulted in an increase in IL-12 and a decrease in IL-5, suggesting an anti-inflammatory effect of BA. This BA nanoparticles controlled the immunologic inflammatory response in asthma, thus controlling the development of asthma and having therapeutic effects on asthma [155]. BA had multiple pharmacological effects on respiratory diseases. Introducing BA into the design and preparation of liposomes improved oral delivery and tissue distribution, exerted anti-inflammatory effects by decreasing the expression of TNF-α and possessed lung-targeting properties to promote drug enrichment at the disease site [156].

The most serious lung disease was known as lung cancer. The active ingredients of natural products were extensively studied owing to their promising antitumor activity. The triterpenoid components UA and astragaloside IV (AS-IV) had therapeutic potential for non-small cell lung cancer (NSCLC). However, bad water solubility and low targeting were shared problems faced by active small molecules. Hyaluronic acid-modified UA and AS-IV-loaded polydopamine (PDA) nanomedicine (UA/(AS-IV)@PDA-HA) not only increased the water solubility of UA and AS-IV, but also improved their active targeting ability. It also achieved enhanced UA-mediated cytotoxicity and anti-metastatic ability against NSCLC cells and increased AS-IV-mediated autoimmune response to tumor-associated antigens, which further synergized with UA to inhibit NSCLC metastasis [157].

TP had anti-inflammatory and immunosuppressive effects and might also show therapeutic effects on tumors, yet has severe acute cytotoxicity [158]. Anti-carbonic anhydrase IX (CAIX) antibody significantly recognized CAIX overexpressed on the surface of lung cancer cells. Therefore, liposomes with CAIX were effective in killing cells of CAIX-positive human NSCLC cells and enhanced anti-cancer effects [159].

Alternatively, drug resistance of lung cancer cells was a major cause of its therapeutic failure. CUR had a wide range of biological activities and significantly inhibited tumor growth, invasion and metastasis in lung cancer and overcame treatment resistance [160]. Silver nanoparticles decorated in SBA-15 mesoporous silica coated with melanin-like PDA acted as nanocarriers and CUR was loaded into the mesopore through the non-covalent interaction of CUR with the PDA coating (Fig. 6a). This composite improved drug resistance in lung cancer cells, reduced off-target drug toxicity and increased chemotherapeutic efficiency of paclitaxel-resistant NSCLC cells (A549/TAX) through dual stimulation of response (pH and ROS) release [152].

Besides treating the above-mentioned diseases, natural product-based nanomedicines had therapeutic effects on Idiopathic pulmonary fibrosis (IPF). IPF was a diffuse parenchymal lung disease with few therapeutic options but was serious and fatal. Arctiin (ARC), which had potent anti-inflammatory, anti-aging and anti-fibrotic properties, might be a potential therapeutic agent for IPF. Alveolar epithelial type 2 (AEC2) cellular senescence was associated with IPF. IPF and ARC-encapsulated DSPE-PEG bubble-like nanoparticles (ARC@DPBNPs) not only improved the hydrophilicity of ARC, but also achieved high lung delivery efficiency. This inhibited the p38/p53/p21 pathway and attenuated senescence and lung fibrosis in AEC2. Therefore, ARC@DPBNPs were nanomedicines with therapeutic potential for IPF [161].

CPT prodrug (EB-ss-CPT) and podophyllotoxin (PPT) were assembled into a nanomedicine ECT Nano. It has high synergistic effect on NSCLC and reduces toxic side effects, which has great reference value for the research and development of combined nanomaterials [151].

Natural product-based nanomedicines against kidney disease

TCM theory calls the kidney “The foundation of innateness” because it has extensive functions, including reproduction, fluid metabolism and respiratory function. Problems with the kidney often trigger nephritis, kidney stones, uremia, etc. [162]. Traditional treatment focuses on drug therapy, nutritional supplementation and replacement therapy. In recent years, the research of nanomedicine in renal diseases has made some progress [163, 164], which is promising to improve the problems of certain systemic drug toxicity, short half-life, and poor renal accumulation that existed in traditional drug therapy (Fig. 7).

Fig. 7

Copyright The author(s). b Route of synthesis and mechanism of function of SU-MNC [166]. Copyright XXXX American Chemical Society. c Synthesis route and mechanism of action of PLGA-Gyp XLIX NPs [167]. Copyright 2021 Elsevier B.V

Several nanomedicines based on natural products against kidney disease. a Synthesis route and mechanism of action of KLPPR [165].

There are essentially three ways in which nanomedicines could be used to treat renal diseases, on the one hand, the drug was loaded and thus entered the disease site to exert therapeutic effects. Acute kidney injury (AKI) often occurred in patients with cardiovascular disease due to the use of iodine contrast media (ICM) for imaging and interventional therapy. The strategy of encapsulating ginsenoside Rb1 (GRb1) in PEG/polylactic acid-glycolic acid (PLGA) nanocarriers not only improved the bioavailability of the active ingredient, but also increased renal aggregation of the drug [168]. Further, to surmount the obstacles of inefficient uptake of nanoparticles by renal cells and rapid excretion of nanoparticles in urine, a two-step nanoparticle cascade concept had been proposed by a team to enhance the uptake by renal cells by controlling the nanoparticle size and targeting. Kidney-targeted rhein-loaded lipopolysaccharide particles (KLPPR) with a yolk-shell structure consisting of a polycaprolactone-polyethyleneimine (PCL-PEI)-nucleated, kidney-targeting peptide (KTP)-modified lipid layer was prepared [169], which allowed for the high loading of RH, sustained release, good stability and biocompatibility, and rapid cellular uptake in HK-2 cells (Fig. 7a) [165].

On the other hand, the active ingredients of natural products combined with the substance with targeting effect were delivered to the lesion site for action. The main pathological feature in the development of chronic kidney disease was renal fibrosis. PLGA contributed to the targeting of gibberellin (Gyp) XLIX to unilateral ureteral occlusion (UUO) kidneys, resulting in the treatment of renal fibrosis. It was found that the relative uptake of PLGA-DiR NPs into fibrotic kidneys was 11-fold higher than that of free DiR on the third day of administration and continued to fluoresce until the seventh day of detection. Poly(lactic-co-glycoside)-Gyp XLIX nanoparticles at around 120 nm were more effective in inhibiting renal fibrosis, reducing collagen deposition and attenuating tubular necrosis compared to Gyp XLIX (Fig. 7c) [167].

Finally, the active ingredients of natural products could also be used as functional carriers to load chemotherapeutic agents into the kidney to exert synergistic therapeutic effects. Micellar nanocomplexes (SU-MNC) loaded with sunitinib using PEG-coupled epigallocatechin-3-o-gallate (PEG-EGCG) as a carrier were demonstrated to exhibit 5.1-fold higher tumor accumulation in human renal carcinoma cells A-498 (10.8 ± 2.4% ID/g) than that of SU alone (2.1 ± 0.5% ID/g) and also showed significantly higher tumor growth inhibition effect (75.4%) than that of SU alone (0.9%). The MNC carrier resulted not only in enhanced tumor targeting, but also in a 0.5-fold, 0.7-fold and 0.4-fold reduction of SU accumulation in heart, lung and muscle, respectively, suggesting enhanced biosafety and reduced off-target (Fig. 7b) [166].

Natural product-based nanomedicines against mammary gland disease

Breast cancer refers to the category of "breast rock" in TCM theory. Breast cancer is a malignant disease that seriously threatens women's health, with a high morbidity rate [170]. The treatment of breast diseases with natural products has fewer side effects and more tolerable psychological expectations, thus gaining more respect from patients and medical researchers. Recently, research on nanomedicines in breast diseases has made some progress, which is expected to improve the problems of systemic drug toxicity, short half-life and low breast accumulation that exist in traditional drug therapy [171, 172] (Fig. 8).

Fig. 8

Copyright The Royal Society of Chemistry 2020. b Synthesis route and mechanism of action of QDAF@Cur, confocal microscopy diagram demonstrating its cellular uptake [174]. Copyright 2020 The Author(s). c Synthesis route and mechanism of action of Nab-PTX-PA, and the figure demonstrates its tumor volume size after treatment [175]. Copyright 2021 The Author(s). d CQM's synthesis route and mechanism of action, the graph demonstrated the concentration of its QM in different organs [176]. Copyright 2020 Huang, Chen, Zhu and Huang

Several nanomedicines based on natural products against mammary gland disease. a Synthesis route and mechanism of action of FA-R8-LPs-DOX, and confocal micrographs demonstrating cellular uptake and intracellular localization of FA-R8-LPs-DOX [173].

In order to achieve the anti-cancer effect of "combined toxicity reduction and targeted synergism", the active components of Tripterygium wilfordii and Dendrobium were self-assembled through intermolecular forces (such as hydrogen bonding, hydrophobic action and van der Waals force) to produce celastrol and erianin nanoparticles (CEN). Through research, it had been found that CEN had a significant killing effect on breast cancer cells [177].

Paclitaxel (PTX) was an active ingredient of natural products with excellent effect in treating breast cancer. Nanoparticles bound to palmitic acid make paclitaxel significantly more lipid-soluble, avoiding irritation of blood vessels and damage to the organism. At the same time, albumin with targeting effect was introduced, which allowed for a dual targeting effect. The precise targeting of such nanoparticles effectively enhanced anti-tumor activity (Fig. 8c) [175].

DTX had significant advantages in the treatment of metastatic breast cancer and was often used as the standard chemotherapy for triple-negative breast cancer. However, it was insoluble in water and had serious side effects. An RGD peptide-modified lipid nucleic micelle was designed and synthesized. The RGD peptide could recognize αVβ3, which was expressed in breast cancer cells, especially metastatic breast cancer cells, then in normal cells and consequently possessed active targeting properties. This allowed the drug to be precisely transported to the tumor site, thereby increasing the effectiveness of the treatment and reducing side effects [178]. In another nano-delivery system, the folate receptor (FR) was introduced by taking advantage of the specific overexpression of FR on the surface of malignant tumor cells. It could aggregate the drug in the target area of the lesion, obtaining good stability, avoiding the damage to normal tissues, effectively inhibiting tumor growth and improving the therapeutic effect [179].

Qu was known to relieve cough and asthma, lower blood pressure and treat tumors. However, it was almost insoluble in water and had a weak targeting ability for tumors. The biomimetic nanoparticles were designed to obtain targeting of tumor tissue by coating the surface with outer cancer CM, which was effective in inhibiting tumor growth (Fig. 8d) [176, 180].

Astragalus polysaccharide (APS) could play an immunomodulatory role. Qu possessed anti-inflammatory, antioxidant and anti-tumor effects, but had the disadvantages of poor solubility and low bioavailability [157]. There were FR expressed on the surface of tumor cells and FA as an important ligand was capable of binding specifically to them and thus exerting tumor-targeting effects. Therefore, CUR, APS, Qu and FR were jointly prepared to synthesize QDAF@Cur nano-pomegranates, which could be targeted to aggregate in breast tumors. It not only improved the solubility of the active ingredients of the herbs, but also exerted stronger anti-breast tumor activity (Fig. 8b) [174].

An innovative nano system ((TP + A)@TkPEG NPs) encapsulated the photosensitizer aggregation-induced emission and autophagy regulator TP within ROS-responsive nanoparticles. This system not only effectively increased intracellular ROS levels and activated ROS-responsive TP release, thereby inhibiting 4T1 cell proliferation in vitro, but also significantly reduced the transcription and protein expression of autophagy-related genes in 4T1 cells, ultimately promoting cell apoptosis. Furthermore, the nano system demonstrated the capability to effectively target the tumor site, achieving efficient tumor suppression and prolonging the survival time of 4T1 mice [181].

EMO inhibited tumor angiogenesis and cell proliferation as well as promoted tumor cell apoptosis. RGD specifically bonded to the integrin αvβ3 receptor overexpressed on breast cancer cells and R8 was a cell-penetrating peptide. Therefore, R₈GD-modified daunorubicin liposomes and EMO liposomes exhibited targeting and inhibitory effects on breast tumor cells [182].

Ginsenoside Rh2 was able to interact with tumor cell glucose transporters and liposomes might be targeted to tumors through effects such as EPR effect, significantly enhancing the accumulation of liposomes in tumors. Therefore, Paclitaxel-Rh2-lipo could be targeted to breast tumors to enhance the activity of anticancer drugs [183].

AS-IV exhibited potent antioxidant activity and toxicity-reducing effects on chemotherapeutic drugs, but its water solubility was poor. Ordinary liposomes based on the EPR effect could passively target tumors, but had the disadvantages of poor selectivity, easy diffusion and leakage. FA bound to FR, which was highly expressed on the surface of many malignant tumor cells. Taken together, the FA-modified liposomes prepared by introducing AS-IV allowed the co-administration of two different drugs and showed good tumor targeting and anti-tumor effects (Fig. 8a) [173].

A multifunctional bionic liposome loaded with gambogic acid (G/R-MLP) was prepared by ginsenoside Rg3 (Rg3) instead of cholesterol and cancer cell membrane coating to play a synergistic role in anti-triple-negative breast cancer [184].

Biomimetic nanoparticles were prepared by coating silybin with modified erythrocyte membrane, which broke through the drug resistance mechanism of triple negative breast cancer and significantly improved the therapeutic effect. [185].

Natural product-based nanomedicines against colon disease

Colon cancer as a common malignant tumour of the digestive tract occurring in the colon area has a high morbidity and mortality rate [169, 186]. In recent years, excellent specific therapeutic effects and avoidance of other side effects have been demonstrated in studies of targeted treatment of colon diseases using the active ingredients of natural products (Fig. 9).

Fig. 9

Copyright The Author(s) 2021. b Synthetic route and mechanism of action of EMO-NYPs [188]. Copyright 2021 Elsevier Ltd. c Synthesizing route and mechanism of action of RGD-ATST/TAGE CNPs [189]. Copyright 2020 Bao et al.

Several nanomedicines based on natural products against colon disease. a The synthesis line and mechanism of action of PSVII@MCP-CaP [187].

Oral treatment of ulcerative colitis (UC) faced several obstacles and the problem of how to safely deliver and accumulate drugs to the lesion site remains to be solved. Studies demonstrated that lipid-derived nanoparticles of Lycium barbarum (LB) (LBLNs) with a size of approximately 189.2 nm exhibited favorable therapeutic effects in UC. The mechanism of action was related to the nanoparticles targeting and internalizing UC treatment-related target cells, thereby inhibiting the secretion of pro-inflammatory cytokines and up-regulating the expression of anti-inflammatory factors. Experiments in mice demonstrated that oral administration of LBLNs specifically accumulated in inflamed colonic tissues, further attenuating UC-related symptoms such as weight loss, histopathological manifestations and ulceration [190]. The study also showed that Man-CUR NYPs, a supramolecular nanoparticle loaded with ROS scrubbers via host–guest interacting D-mannose (Man), can be targeted for aggregation at the site of inflammation. The nanoparticles provided excellent oral administration and stable accumulation in the colon for effective treatment of UC. In a DSS-induced mouse model of colitis, Man-CUR NYPs reduced oxidative stress, exerted a therapeutic effect in inflammation, and improved damaged colonic tissues [191]. EMO, with its anti-inflammatory and mucosal repairing effects, was one of the commonly used drugs for the treatment of UC. Lactoferrin, which targeted intestinal epithelial cells and YPs (yeast cell wall particles), which naturally targeted macrophages, were introduced in the preparation of the nano-oral delivery system to obtain more stable dual-targeted nanoparticles (EMO-NYPs) and thus better repaired intestinal mucosa (Fig. 9b) [188].

Colon cancer was a malignant tumor and human epidermal growth factor receptor 2 (HER2) was overexpressed in some colon cancer patients. Therefore, a TPL-loaded HER2-targeted nanoparticle (TPLNP) drug delivery system was prepared. TPLNP had a higher therapeutic efficiency for colon cancer treatment compared to the free TPL-treated group. In vivo and in vitro, TPLNP possessed favorable colon cancer targeting properties, hence it could effectively inhibit HER2 overexpression and BRAF-mutated colon cancer [192]. Paris saponin VII (PSVII) played an anti-colon cancer role by inhibiting the growth of colon cancer cells, reducing the spread of drug-resistant colon cancer cells and promoting the apoptosis of drug-resistant colon cancer cells. Modified citrus pectin (MCP) could bind to Gal-3, which was highly expressed on the cell membrane of drug-resistant colon cancer cells. Therefore, the addition of MCP to nanoparticles could induce apoptosis of drug-resistant colon cancer cells by stimulating mitochondria mediated apoptosis pathway (Fig. 9a) [187]. In addition, tangeretin (TAGE) suppressed colon cancer cell proliferation and HCC proliferation. The specific expression of αvβ3 integrin receptor existed in some tumor cells and some synthetic cyclamated arginine-glycine aspartate sequences (RGD) were highly binding to αvβ3. The prepared nano delivery system RGD-ATST/TAGE CNPs had been proved to accurately target colon cancer, with high aggregation at the tumor site, which could significantly inhibit tumor growth in vivo, providing more possibilities for nano therapy of colon cancer (Fig. 9c) [189].

Chronic and debilitating inflammatory bowel disease (IBD) requires more effective treatments. A specific group of self-assembled nanoparticles (GDNPs 2) derived from edible ginger could effectively target the colon after oral administration. The nanoparticle was non-toxic, effectively responds to acute colitis, enhances intestinal repair, and may improve the prevention and treatment of IBD-related cancers [193]. Ginger contained a variety of bioactive components, such as gingerol, gingerene, sesquiterpenes, etc., which could be spontaneously assembled by non-covalent bonding forces under certain conditions.

Berberine (BBR) and magnoliol treated UC by self-assembly into nanostructures in aqueous solution through charge interactions and π-π stacking [51]. This nanostructure had good oral bioavailability and colonic biodistribution, excellent therapeutic effect and high safety [51, 194].

Lentinan contains a large number of hydroxyl groups, which could be combined with the hydrophobic part of ursolic acid (UA) through hydrophobic action and hydrogen bonding force to form stable self-assembled nanoparticles, which could effectively treat colorectal cancer (CRC) [12].

The biomimetic nanoparticles made from extracted cancer cell membrane-coated gambogic acid had low biotoxicity and high tumor targeting ability, and could improve the anti-tumor immune response of colorectal cancer [195].

Natural product-based nanomedicines against others disease

In addition to studies on specific diseases, nanomedicines have shown promising therapeutic effects on other diseases.

BBR molecules were inserted into the layered rhein molecular structure and self-assembled into nanoparticles, which had a strong inhibitory effect on Staphylococcus aureus [196].

The overuse of antibiotics and bacterial resistance had led to an increasing number of deaths from bacterial infections. Gallic acid and BBR were self-assembled to form carrier free nanoparticles (GA-BBR NPs) through electrostatic interactions, π–π stacking and hydrophobic interaction. The experimental results showed that the nanoparticle could block the bacterial translation mechanism, showed strong antibacterial activity against multidrug-resistant Staphylococcus aureus (MRSA), had good anti-inflammatory effect, and had good biocompatibility and safety [197].

BBR and cinnamic acid could be directly self-assembled into nanoparticles (NPS) with good antimicrobial activity through hydrogen bonding and π-π stacking interactions. The results showed that the nanoparticles did not have hemolytic properties, had little toxicity in vivo and in vitro, and had better inhibition effect on multi-drug-resistant Staphylococcus aureus [198].

The electrostatic and hydrophobic interaction between BBR and flavonoid glycosides could be naturally self-assembled into nanoparticles (NPs) and nanofibers (NFs). Compared with BBR, the antibacterial activity of NPs was significantly enhanced, while the antibacterial activity of NFs is much weaker than that of BBR. The results show that the obtained self-assembly had good biocompatibility. This supramolecular self-assembly strategy could be used to construct other nanoscale antibacterial drugs and provided reference for the research of self-delivery drugs for the treatment of bacterial infections [199].

Because Helicobacter pylori is not sensitive to antibiotics, the prevalence of helicobacter pylori infection is increasing year by year. A multifunctional nanomedical drug (BD/RHL ND) containing lipophilic alkyl BBR derivatives (BD) and rhamnoolipid (RHL) was self-assembled through electrostatic and hydrophobic interaction, which showed a strong ability to eradicate H. pylori biofilm [200]. BBR and hesperetin (HST) directly self-assemble to form binary carrier free multifunctional spherical nanoparticles through non-covalent bonds (electrostatic interactions, π–π stacking and hydrogen bonding), which exerted synergistic anti-inflammatory activities and repaired the damaged intestinal barrier [201].

BBR and chlorogenic acid (CGA) could be self-assembled to synthesize supramolecular nanoparticles, which showed better inhibition against Staphylococcus aureus and MRSA and promoted wound healing [202].

The development of self-assembled CPT prodrug (CPT-SS-FFEYp-biotin) by combining three strategies of targeted therapy, prodrug design, and drug delivery has been demonstrated to enhance the antitumor activity of CPT while being safer than CPT [203].

Bacterial infection is a serious threat to health. We constructed a near infrared (NIR) responsive carrier free BBR hydrochloride nanoparticle to generate carrier free nanoparticles through electrostatic interactions, π–π stacking and ICG self-assembly of amphipathic ICG. The nanoparticle could be used for synergistic antibacterial of infected wounds and promoted the healing of infected wounds [204].

There might be hydrogen bonding between the hydroxyl group in baicalin molecule and the amino group in BBR molecule, resulting in tight binding of the two, and self-assembly under the combined action of electrostatic and hydrophobic, which could effectively solve the diarrhea-oriented irritable bowel syndrome through synergistic treatment [205]. And ROS-responsive biomimetic natural product-based nanomedicines nano-preparation made of extracted neutrocyte cell membrane coated with leonurine could achieve synergistic treatment of endometriosis with excellent biosafety [206].

Polysaccharide components with enhanced antitumor activity were found to improve the immunosuppressive tumor microenvironment. ASP inhibited tumor growth and bolstered anti-tumor immunity. A targeted enzyme-sensitive nano-delivery system, AP-PP (polypeptide)-DOX (adriamycin), was synthesized using ASP as a carrier, demonstrating superior anti-tumor efficacy with high drug loading and tumor targeting [207]. TAN inhibited prostate cancer cell growth, with PSMA present on tumor cells. Targeting prostate cancer was achieved by incorporating a PSMA-targeting ligand into the lipid nano-delivery system (P-N-DOX/TAN), addressing TAN's non-selectivity and minimizing side effects. This lipid system exhibited stability and synergistic anti-tumor properties [208]. Additionally, metastasis remains a significant challenge in tumor treatment, contributing to tumor progression and recurrence. Diosgenin inhibited metastasis, while DOX induced apoptosis. Consequently, a novel pH-sensitive polymeric drug based on diosgenin NPs was developed to enhance DOX delivery (DOX/NPs) for synergistic cutaneous melanoma treatment. Compared to free DOX, DOX/NPs showed improved accumulation at the tumor site via the EPR effect, significantly inhibiting metastasis, inducing apoptosis, and reducing tumor size and weight through synergistic effects [209].

A combination of paclitaxel and TanIIA exhibited the strongest synergistic effect in inducing apoptosis in human acute promyelocytic leukaemia (APL) cell line NB (4) cells at a molar ratio of 1:1. In order to increase the efficacy and reduce the side effects, an active targeted drug delivery system of MSNs coated with FA-modified PEGylated lipid layer (LB) membranes (FA-LB-MSNs) was established for loading the drugs. The group of paclitaxel- and TanIIA-loaded FA-LB-MSNs could be targeted to the tumor and significantly induced apoptosis and inhibited tumor growth [210]. Benzene could cause acute myeloid leukaemia. Carboxymethyl cellulose (CMC) encapsulating methanolic extracts of eucalyptus, rose and thyme on silica nanocarriers (SNBs) attenuated benzene-induced haematotoxicity effects, thereby enhancing their targeted delivery. In vivo experiments revealed that the plant extract SNBs had an attenuating effect on benzene-exposed rats by reducing the increase in liver and spleen weights and a significant decrease in differential white blood cell (WBC) counts [211].

Cutaneous melanoma was the deadliest skin cancer with high malignancy, early metastasis and high mortality. Erythrocytes and macrophages fused into hybrid membranes (EMHM) encapsulated rhodopsin into hybrid membrane-encapsulated nanoparticles and then introduced glycyrrhizin to increase the solubility of rhodopsin. Ultimately hybrid membrane-encapsulated nanoparticles of rhodopsin and glycyrrhizin (EG@EMHM NPs) were prepared for the treatment of melanoma. It was found that the cell inhibitory effect (1.166 mg/ml) of biomimetic nanoparticle tumor was two times higher than that of free rhodopsin. The photodynamically-mediated EG@EMHM NPs induced early apoptosis of B16 and exerted a significant anti-tumor effect on melanoma via the BAX and BCL-2 pathways [212].

In order to improve the limitations of conventional dressings for the treatment of MRSA infections in terms of their mono-functionality, insufficient drug release, poor biosafety, or high rate of drug resistance, a novel wound dressing consisting of glycopyrrolate and tryptophan-sorbitol carbon quantum dots (WS-CQDs) was developed. The prepared glycopyrrolate/WS-CQDs hydrogel (GA/WS-CQDs-gel) showed superior in vitro anti-MRSA efficacy compared to common antibiotics. The WS-CQDs in the gel were released continuously for 60 h with a high cumulative release rate (more than 90%). Glycopyrrolate/WS-CQDs dressings reduced the expression of inflammatory factors (TNF-alpha, IL-1beta and IL-6) in infected mice with little systemic toxicity, demonstrating the high suitability of glycopyrrolate/WS-CQDs dressings for the healing of MRSA-infected wounds and their potential for clinical translation [213].

A synergistic effect of simultaneous inhibition of DOX resistance (MCF-7/ADR cells), reduction of cardiotoxicity (H9c2 cells) and enhancement of therapeutic efficacy (MCF-7 cells) in the treatment of breast cancer was achieved by co-administration of DHA and tetrahydroartemisinin [214]. DHA-TET liposomes prepared using the PH response of the tumor microenvironment showed a nearly 50-fold improvement in the reversal of DOX resistance and uptake (resistance index RI of 46.70) and remained stable for 6 months at room temperature [215].

A common complication of diabetes mellitus was the decrease in antioxidant capacity and the development of microinflammatory syndrome. The pterostilbene was developed as poly (3-acrylamidophenylboronic acid-b-pterostilbene) (p(AAPBA-b-PTE) NPs) for disease treatment due to a wide range of biological applications, such as antioxidant and amelioration of inflammatory responses [55]. Insulin-loaded NPs with pH and glucose sensitivity have been shown to be safe, non-toxic and effective in lowering blood glucose, improving antioxidant capacity and reducing inflammation in both in vivo and in vitro experiments [216].

Compared with modern therapies, the active ingredients of TCM in natural products can provide a wide range of bioactive molecules, which is the material basis for preventing and treating more diseases. They have a wide range of pharmacological effects and can be used to target individual symptoms. Moreover, their multi-target synergies show a more flexible and comprehensive therapeutic effect in treating disease. In addition, they have better safety, no obvious damage to the body's physiological functions, and few side effects. When used externally, it can avoid gastrointestinal discomfort or liver and kidney burden caused by oral administration, and is more suitable for long-term treatment and patients with sensitive constitution. They are also self-targeting, which can significantly reduce side effects and enhance treatment effectiveness. They can also make the animal body produce specific and non-specific immune function and enhance immunity. To sum up, the active ingredients of TCM in natural products has unique advantages in ensuring safety, reducing side effects, conducting comprehensive conditioning, improving immunity, and improving treatment effect [217,218,219,220].

However, there are also shortcomings such as poor solubility, permeability and stability, low bioavailability and poor pharmacological activity [65, 221]. Natural product-based nanomedicines are not only simply combining the advantages of natural products and nanotechnology, but also making up for each other's disadvantages with their advantages to obtain better results [222]. Self-targeting natural product-based nanomedicines have shown obvious advantages for solving the difficult problems of disease delivery and treatment. Firstly, natural product nanomedicine has smaller particle size, which can be easily absorbed by the human body and improve its bioavailability. Second, the toxic components of natural products can be reduced by modification or combination, and their safety can be improved. Third, enhanced self-targeting may reduce toxic side effects and improve therapeutic efficacy. Fourth, the composition structure was optimized, the stability was improved and the shelf life was prolonged. Fifth, the nanoformulation type is more comfortable to use and more acceptable to patients [223,224,225].

Safety evaluation of natural product-based nanomedicines

So far, the development of natural product-based nanomedicines has mainly been to improve the solubility of insoluble substances and improve targeting, and more importantly, to ensure the safety of use. Natural product-based nanomedicines not only enhance the efficacy of natural product compared to single application, but also ensures a certain degree of safety, largely reduces or avoids the toxicity of non-diseased areas and also reduces the toxicity of natural product itself [226]. Dual-loaded nano delivery systems enhanced the therapeutic effect of drugs on tumors through synergistic action and reduced the toxic side effects of drugs on normal tissues. Paclitaxel-siRNA vascular endothelial growth factor-NPs were found to exert anti-tumor effects by inhibiting the formation and development of neovascularization in tumor tissues with a higher in vivo safety profile [227]. Gambogic acid exhibited multi-targeted anti-tumor activity in a wide range of tumors. However, it had poor solubility and no specific effect on tumors. To decrease the inherent limitations of Gambogic acid and to enhance its antitumor activity, liposomes modified with the nuclear targeting peptide CB5005N (VQRKRQKLMPC) were constructed via a PEG linker. It was validated to have satisfied targeting properties, excellent anti-tumor efficiency and significantly reduced toxicity to normal tissues [228]. A pH-sensitive biomimetic nanodrug delivery system based on the fine "core–shell" structure of the erythrocyte membrane was designed by introducing paclitaxel, which had anti-tumor activity. Excellent biocompatibility and sensitivity to the acidic tumor microenvironment effectively prolonged the circulation time of paclitaxel, enhanced the anti-tumor effect, and significantly attenuated the nephrotoxicity induced by paclitaxel [229].

At present, there are many advanced preclinical evaluation methods to study the cytotoxicity and biological distribution of nanomedicine. Hydrogels prepared with chitosan backbone grafted with CGA (CA-ECS), oxidized pullulan polysaccharide (OP), and zinc ions (Zn²⁺) were applied to a rat model of full-thickness skin wounds infected with Staphylococcus aureus. Animal experiments showed that the hydrogel had excellent anti-inflammatory activity and accelerated wound healing [89]. Luteolin was loaded into hyaluronidase nanoparticles and applied to mice models of idiopathic pulmonary fibrosis. Studies showed that the nanoparticles could improve lung function and survival rate, and reduce lung injury [89, 230, 231]. Ellagic acid enhanced the biocompatibility and bioactivity of multi-layer core–shell gold nanoparticles to ameliorate myocardial infarction injury, which was validated in zebrafish larval model and mouse model [89, 230, 231]. Through computer simulation and in vitro experiment, it was found that BBR and MAG could spontaneously form stable nanoscale self-assembly in aqueous solution [194]. A three-dimensional high-throughput hepatocyte microarray model was constructed with collagen hydrogel to compare the hepatotoxicity of KMSHT and Kunxian capsule (KXJN) [232]. The organoid model, sterile mouse model and cells of cancer cells from human CRC patients were used to explore the effect of Chinese medicine Pien-intestinal flora interaction on the prevention of CRC [233]. Advanced, ethical, and model-rich preclinical evaluation provides important experimental data and theoretical basis for studying drug efficacy, mechanism of action, evaluating safety, optimizing drug design, and supporting clinical translation.

Natural product-based nanomedicines are an emerging pharmaceutical technology that combined the biological activities of natural products with the advantages of nanotechnology to provide new possibilities for drug research and treatment, and has caused a paradigm shift in the field of healthcare. However, fundamental barriers that hinder or delay the clinical translation of natural product-based nanomedicines remain [234]. It should be noted that natural product-based nanomedicines were still in the development stage, related research was still deepening, and its clinical application still faces challenges in terms of technology, safety, production scale. First, there were many technical problems in the research and development of natural product-based nanomedicines, such as the stability of nano particles, the speed and location of drug release, etc. Second, toxicological studies on nanomedicine based on natural products were insufficient, and the understanding of their potential risks is not sufficient. The safety evaluation methods of traditional drugs are not fully applicable to nanomedicine, and new safety evaluation methods are still being explored [235]. Third, nanomedicine of natural products is still in the research stage and has not been large-scale mass production, so the problem from the laboratory to the industrial stage is not clear. Fourth, relatively few nanomedicine products have received clinical approval. Currently approved nanomedicine mainly relies on passive targeting (such as EPR), however, due to tumor heterogeneity and other factors, EPR in the human body may be difficult to effectively deliver drugs. However, the development of active targeted nanomedicine lags behind that of passive targeted nanomedicine, most of which are still in the pre-clinical research stage. Nanomedicine mediated by natural products is a new dosage form, and its clinical research evaluation model has not been reported [236]. To sum up, the clinical application of nanomedicine based on natural products is very rare, among which the nanomedicine based on the active ingredients of TCM is even less, and these difficulties need to be further overcome in future research to promote the safe, effective and widespread application of natural product-based nanomedicines [237].

Discussion

The research and application of natural product-based nanomedicines remain in early development compared to other drug types, with significant challenges ahead for clinical use. 1. Holistic synergy is insufficient. Recent studies have identified pharmacodynamic markers from numerous active natural product ingredients, yet most nanomedicines overlook multi-component synergistic effects, focusing instead on single ingredient pharmacology. 2. Dependence on functional nano carriers is high. The diverse physicochemical properties of natural product components often lead to poor solubility and low bioavailability. While nanotechnology has mitigated some of these issues, the construction of nanomedicines heavily relies on functional carriers, which can overshadow the pharmacological contributions of the natural product components. 3. Self-targeting properties remain underutilized in natural product-based nanomedicines, despite the inherent targeting capabilities of certain active ingredients. Current research often focuses on membrane protein modifications and ligand interactions, neglecting the potential of these natural properties. 4. Clinical applications of such nanomedicines are limited, with paclitaxel being the only extensively developed compound.

To enhance the development and application of natural product-based nanomedicines, several innovations are necessary. Firstly, combining not only single effective ingredients with nanomaterials but also multiple components can enhance therapeutic efficacy. Secondly, integrating natural product efficacy screening with nanotechnology can lead to nanoparticles with multiple quality markers, optimizing therapeutic outcomes. Thirdly, developing carrier-free natural product nanoparticles can improve drug loading capacity while maximizing the pharmacological effects of active ingredients. Additionally, identifying potent active ingredients with drug-forming capabilities enables the co-development of single or multiple components into clinically viable drugs, addressing the limitations of single-species applications. Finally, Prioritizing safety in nanomedicine is essential. Utilizing the inherent targeting properties of natural products will enhance the development of nanomedicines with reduced off-target toxicity and increased therapeutic efficacy, facilitating future clinical applications.

Conclusion

After the exploration of natural product-based nanomedicines, this review systematically presented an overview of the latest research progress of natural product-based nanomedicines in the treatment of diseases in recent years, mainly from three aspects, namely, the current development status of natural product-based nanomedicines, the therapeutic role played by natural product-based nanomedicines for different organ diseases in a targeted manner and the safety evaluation of natural product-based nanomedicines. A summary has revealed that the current development of natural product-based nanomedicines mainly focuses on terpenoids, alkaloid, phenols and flavonoids. Certain active ingredients with natural targeting properties have been utilized in localized disease treatment, enhancing efficacy while minimizing toxicity by concentrating effects at target sites. Furthermore, combining nanotechnology with potent natural products can further reduce toxicity and improve therapeutic outcomes. Recent studies on natural product-based nanomedicines indicate their superior biosafety, suggesting significant clinical application potential.