Nanodrug delivery systems enhance traditional Chinese medicine treatment of osteoporosis

Abstract

Osteoporosis (OP) is a prevalent chronic metabolic bone disorder characterized by decreased bone mineral density, deterioration of bone microarchitecture, and increased fracture risk. Traditional Chinese medicines (TCM) have demonstrated considerable therapeutic potential in OP management due to their osteogenic and anti-resorptive activities. However, the therapeutic efficacy of TCM is often limited by the drawbacks of conventional delivery systems, underscoring the need for advanced formulation strategies to fully exploit their potential in OP prevention and treatment. In recent years, nanomedicine has emerged as a transformative platform for drug delivery, offering new avenues to enhance the pharmacological performance of herbal medicines. Nano-based delivery systems for anti-osteoporotic herbal compounds provide multiple benefits, including protection of active ingredients from degradation, improved bioavailability, reduced gastrointestinal irritation, and superior therapeutic outcomes. This review provides a comprehensive overview of the nanocarriers employed in the delivery of TCM, summarizes the current status and therapeutic efficacy of herb-loaded nanomedicines in OP management, and discusses the challenges and future directions for clinical translation. By highlighting recent advances and addressing existing hurdles, this review aims to contribute valuable insights for optimizing TCM-based nanotherapeutics in the prevention and treatment of osteoporosis.

Supplementary Information

The online version contains supplementary material available at 10.1186/s11671-026-04786-1.

Introduction

Osteoporosis (OP) is a systemic skeletal disorder characterized by reduced bone mass, deterioration of bone microarchitecture, and increased bone fragility, leading to a markedly elevated risk of fragility fractures [1–2]. Because OP often remains clinically silent until fractures occur, it represents a major health burden in the aging population worldwide. Hip and vertebral fractures are frequently associated with chronic pain, impaired mobility, reduced quality of life, and increased mortality [3–4]. Pathophysiologically, OP results primarily from an imbalance in bone remodeling, in which bone resorption exceeds bone formation, driven by aging, estrogen deficiency, oxidative stress, chronic inflammation, and dysregulation of bone immune homeostasis [5–6].

Current anti-osteoporotic therapies mainly include anti-resorptive and anabolic agents, such as bisphosphonates, selective estrogen receptor modulators, denosumab, and parathyroid hormone-related drugs. Although these agents can reduce fracture risk, their long-term clinical application is often limited by adverse effects, insufficient tissue targeting, high treatment burden, and poor patient adherence [7–8]. Moreover, OP is a multifactorial disease involving osteoclast overactivation, impaired osteoblast function, stem cell dysfunction, insufficient angiogenesis, and disruption of the bone microenvironment, indicating that single-target therapies may not adequately address its complex pathogenesis [9].

Traditional Chinese medicine (TCM) has attracted increasing attention because of its multi-component and multi-target therapeutic properties. TCM-derived extracts and active compounds can regulate osteogenesis, osteoclastogenesis, inflammation, oxidative stress, and osteoimmune balance through signaling pathways such as OPG/RANKL/RANK, Wnt/β-catenin, and BMP/Smads [10–12]. However, many TCM compounds suffer from poor water solubility, low bioavailability, rapid metabolism, and insufficient bone accumulation, which limit their clinical application [13]. Nano-drug delivery systems (NDDSs) provide an effective strategy to overcome these limitations by improving drug stability, prolonging circulation time, enabling controlled release, and enhancing bone-targeting efficiency [14–16].

Although previous reviews have separately discussed TCM for osteoporosis or nano-drug delivery technologies, a comprehensive evaluation integrating TCM-derived compounds, bone-targeted nanocarriers, osteoimmune regulation, and translational perspectives remains lacking. In addition, emerging platforms such as herb-derived exosome-like nanovesicles, biomimetic carriers, and stimuli-responsive delivery systems have not been systematically summarized in the context of osteoporosis therapy. Therefore, this review comprehensively discusses the application of NDDSs for TCM-based osteoporosis treatment, with particular emphasis on mechanistic advantages, bone microenvironment responsiveness, translational potential, and current limitations. By integrating material science, bone-targeting strategies, TCM pharmacology, and translational considerations, this review aims to provide a more comprehensive framework for the future development of clinically translatable nano-therapeutics for osteoporosis.

Application advantages of NDDSs

NDDSs have emerged as an effective strategy to overcome the limitations of conventional pharmacotherapy in OP, particularly in long-term treatment scenarios characterized by poor tissue selectivity and insufficient drug accumulation in bone. Through rational design of material composition, structure, and surface functionality, NDDSs can exploit the unique physicochemical properties of bone tissue and the osteoporotic microenvironment, thereby enabling enhanced delivery efficiency and therapeutic precision [17] (As shown in Fig. 1).

Fig. 1.

Schematic illustration of representative nanocarrier systems applied in the treatment of osteoporosis. The figure depicts various nanocarrier types, including lipid-based nanocarriers (liposomes, solid lipid nanoparticles), polymer-based nanoparticles (chitosan, PLGA nanoparticles), inorganic nanoparticles (mesoporous silica, hydroxyapatite, graphene oxide, metal–organic frameworks), and biological nanovesicles (exosomes)

A key advantage of NDDSs lies in their bone mineral affinity, which enables targeted drug accumulation in skeletal tissue. Bone is primarily composed of hydroxyapatite (HAp), providing a natural binding substrate for nanocarriers functionalized with bone-seeking ligands such as bisphosphonates, acidic oligopeptides, or calcium-binding groups [18]. These modifications facilitate preferential localization of nanoparticles at sites of active bone remodeling, significantly increasing local drug concentration while reducing systemic exposure. Such affinity-driven targeting enhances therapeutic efficacy and minimizes off-target toxicity, which is particularly critical for chronic diseases like OP.

NDDSs also enable microenvironment-responsive drug delivery, particularly in response to the acidic conditions of osteoclast resorption lacunae. During bone resorption, osteoclasts generate localized acidic microenvironments (pH ~ 4.5–5.5), which can be exploited by pH-sensitive nanocarriers to achieve site-specific drug release [19]. In parallel, NDDSs can modulate the osteoimmune microenvironment, a key regulator of bone remodeling. By delivering bioactive agents that promote macrophage polarization from the pro-inflammatory M1 phenotype to the pro-regenerative M2 phenotype, nanocarriers can create a microenvironment favorable for osteogenesis and angiogenesis. Additionally, the co-delivery of anti-inflammatory agents, antioxidants, or gene regulators enables suppression of chronic inflammation and oxidative stress, further contributing to bone homeostasis.

Another important advantage of NDDSs is their capacity for long-term sustained and controllable drug release, which is essential for the management of chronic conditions such as osteoporosis [20]. By tuning carrier composition, degradation behavior, and structural design, NDDSs can maintain stable therapeutic drug levels over extended periods, reduce dosing frequency, and improve patient compliance [21]. Compared with conventional formulations that often exhibit rapid clearance and fluctuating plasma concentrations, NDDS-based systems provide more consistent pharmacokinetic profiles. Furthermore, the incorporation of stimuli-responsive mechanisms—such as pH, reactive oxygen species (ROS), or enzyme-triggered release—enhances spatiotemporal control over drug delivery, allowing precise adaptation to dynamic pathological conditions.

Types of nano-drug delivery carriers for osteoporosis therapy

NDDSs have emerged as a promising strategy for OP therapy because they can substantially improve the pharmacokinetic behavior, tissue distribution, and therapeutic efficacy of bioactive agents. Through rational engineering of carrier composition, nanostructure, and surface properties, NDDSs can enable sustained or stimuli-responsive drug release, enhance drug accumulation in bone tissues, and reduce systemic adverse effects. These advantages are particularly relevant in osteoporosis, where long-term treatment, poor tissue selectivity, and limited local drug exposure remain major challenges. According to their material composition and functional features, the nanocarriers currently explored for OP treatment can be broadly categorized into inorganic nanocarriers, organic nanocarriers, biologically derived nanocarriers, and bone-targeted functionalized nanocarriers (As shown in Table 1).

Table 1.

Classification of nano-drug delivery systems for osteoporosis therapy and their design characteristics. This table summarizes the major categories of NDDSs applied in OP therapy, including inorganic nanocarriers, organic nanocarriers, biological-derived nanocarriers, and bone-targeted functionalized nanocarriers. For each carrier type, the material composition, key design features, underlying mechanisms, and representative application cases are presented

Carrier type	Material composition	Design features	Mechanism	Representative application cases
Inorganic Nanocarriers	nano-HA, MSNs, GO, MOFs	High chemical stability, controllable structure, large surface area, porous, strong bone affinity	Support osteoblast adhesion and proliferation; achieve sustained drug release; promote bone formation and inhibit bone resorption	Nano-HA scaffolds for bone defect repair; MSNs for multi-drug delivery to modulate bone microenvironment; GO composite scaffolds for prolonged drug release and dual osteogenic/anti-resorptive effects; Zn-MOF/Ral nanosheet coating enhances bone regeneration and inhibits bone resorption
Organic Nanocarriers	Biodegradable polymers (PLGA, PCL), lipid nanoparticles, liposomes	Biodegradable, biocompatible, easily functionalized, tunable release	Sustained drug delivery; improve in vivo stability and circulation; allow co-delivery of multiple drugs	PLGA nanoparticles carrying ALN and nMgO combined with bone cement for defect repair; liposomes improving drug stability and bone-targeted delivery
Biological-derived Nanocarriers	Exosomes, cell membrane-derived vesicles	Natural membrane structure, low immunogenicity, high in vivo stability, intercellular delivery	Deliver payloads to osteoblasts or BMSCs; activate Wnt/Î2-catenin and BMP/Smads signaling; inhibit osteoclast differentiation; regulate inflammation and angiogenesis	Bone-targeted exosomes (BT-EXO-Shn3) delivering Shn3 siRNA to enhance osteogenesis and inhibit osteoclasts; engineered miRNA-335-3p exosomes (O-Exos) increase bone density and trabecular number in OP mouse models
Bone-targeted Functionalized Nanocarriers	Bisphosphonate-modified nanoparticles, bone-targeting peptide-functionalized carriers, responsive MOFs	Surface functionalization with bone-affinity ligands, microenvironment-responsive release (pH/ROS/enzyme), multi-drug loading	Achieve active drug accumulation in bone; inhibit osteoclasts and promote osteogenesis; modulate local immune microenvironment and angiogenesis	Zn-MOF/Ral nanosheet coating for local release of Zn2+ and Raloxifene on titanium screws, enhancing trabecular thickness and new bone volume; bone-targeted nanoparticles delivering calcitonin or ALN for dual osteogenic and anti-resorptive effects

Inorganic nanocarriers

Inorganic nanocarriers have attracted considerable interest in OP treatment because of their high structural stability, tunable physicochemical properties, and, in some cases, intrinsic affinity for bone tissue. Among them, nano-hydroxyapatite (nano-HA) is one of the most extensively studied materials, as it closely resembles the mineral phase of native bone matrix [23]. This compositional similarity confers excellent biocompatibility, osteoconductivity, and bone-binding capacity. When fabricated into nanostructured porous systems with a high specific surface area, nano-HA can serve not only as a drug reservoir for sustained release but also as a favorable substrate for osteoblast adhesion, proliferation, and matrix deposition, thereby supporting both local drug delivery and bone regeneration [24].

Mesoporous silica nanoparticles (MSNs) represent another important class of inorganic nanocarriers [25]. Unlike microparticle formulations, which are generally larger and mainly suitable for local depot delivery and long-term sustained release, MSNs possess nanoscale dimensions that favor cellular uptake, tissue penetration, and surface functionalization. Their highly ordered pore structure, large surface area, and tunable pore size allow efficient loading of various therapeutic agents, including small molecules, proteins, and nucleic acids. In addition, the surface of MSNs can be readily modified with functional ligands to improve colloidal stability, prolong circulation, or confer bone-targeting properties [26–27]. These features make MSNs particularly attractive for combination therapy, where coordinated delivery of osteogenic, anti-resorptive, or anti-inflammatory agents may be required to restore bone remodeling homeostasis in osteoporotic lesions.

Graphene oxide (GO) has also been investigated as a multifunctional inorganic platform because of its two-dimensional structure and abundant oxygen-containing functional groups, such as hydroxyl, carboxyl, and epoxy groups. These chemical features permit the loading of both hydrophilic and hydrophobic drugs through π-π stacking, hydrogen bonding, or electrostatic interactions [28]. In addition to its drug-loading capacity, GO-based composites may provide structural cues that support osteoblast adhesion and differentiation. Accordingly, GO-containing scaffolds have shown potential for integrating controlled drug release with osteogenic support, thereby enabling simultaneous suppression of bone resorption and promotion of bone formation [29–30].

Metal-organic frameworks (MOFs), which are self-assembled from metal ions or clusters and organic ligands, have recently emerged as a versatile nanoplatform for skeletal applications [31]. Owing to their crystalline porous architecture, high drug-loading capacity, tunable composition, and modifiable surface chemistry, MOFs can be engineered to incorporate therapeutic ions, osteoinductive factors, or anti-osteoporotic drugs. In the context of OP treatment, these materials provide opportunities for localized and sustained drug delivery while simultaneously contributing bioactive cues that favor bone regeneration [32].

Importantly, the therapeutic advantages of organic nanocarriers are not limited to improving drug solubility and pharmacokinetic behavior. Increasing evidence suggests that these systems can actively regulate intracellular osteogenic signaling pathways by enhancing cellular uptake and prolonging local retention of TCM-derived compounds. For example, sustained intracellular delivery mediated by liposomes, polymeric nanoparticles, and lipid-based carriers can enhance activation of the Wnt/β-catenin and BMP/Smads pathways, thereby promoting β-catenin nuclear translocation, Runx2 expression, and osteoblast differentiation. In addition, controlled-release characteristics of organic nanocarriers contribute to prolonged osteogenic stimulation and improved bone matrix mineralization, which may partly explain their superior therapeutic efficacy compared with free drug administration.

Organic nanocarriers

Organic nanocarriers, mainly based on biodegradable polymers or lipids, constitute another major category of NDDSs for OP therapy. Compared with inorganic systems, organic carriers generally exhibit superior biocompatibility, lower immunogenicity, and greater flexibility in molecular design. These advantages make them particularly suitable for systemic administration and repeated dosing, both of which are often necessary in chronic skeletal disorders.

Polymeric nanoparticles, such as those fabricated from poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), or related biodegradable polymers, are widely used for controlled drug delivery [33–34]. Therapeutic agents can be physically encapsulated within the polymer matrix or chemically conjugated to the carrier backbone, thereby enabling sustained release over extended periods. Importantly, the release kinetics of these systems can be tailored by altering polymer composition, molecular weight, crystallinity, or degradation rate. This tunability allows polymeric nanoparticles to be optimized for different anti-osteoporotic agents with distinct pharmacological and physicochemical properties. Moreover, their gradual biodegradation in vivo minimizes the need for surgical retrieval and reduces the risk of long-term carrier persistence.

Lipid-based nanocarriers, including liposomes and lipid nanoparticles, have also shown considerable promise for OP treatment [35–36]. Their lipid bilayer or lipid matrix structure enables the co-delivery of hydrophilic and hydrophobic compounds, thereby expanding the range of drugs that can be incorporated into a single formulation. In addition, their membrane-like architecture facilitates cellular uptake and intracellular delivery, while also protecting labile drugs from premature degradation. Surface engineering strategies, such as polyethylene glycol (PEG) modification or ligand conjugation, can further improve circulation stability and target specificity [37]. These features are advantageous for enhancing the in vivo performance of bioactive compounds with poor solubility, short half-lives, or limited oral bioavailability.

From a translational perspective, the key strengths of organic nanocarriers lie in their controllable biodegradability, adaptable release profiles, and ease of multifunctional modification. They are therefore particularly well suited for applications requiring precise pharmacokinetic tuning, systemic administration, or multi-drug co-delivery. However, challenges such as burst release, limited loading of certain drugs, storage stability, and scale-up reproducibility remain important considerations in formulation development.

Biologically derived nanocarriers

Biologically derived nanocarriers, especially exosomes and cell membrane-derived vesicles, have emerged as an important frontier in bone-targeted nanomedicine. Because these carriers are derived from natural biological membranes, they possess several intrinsic advantages, including low immunogenicity, favorable biocompatibility, high colloidal stability in biological fluids, and efficient intercellular communication capability. Compared with conventional synthetic nanocarriers, biomimetic vesicles may better evade clearance by the mononuclear phagocyte system, thereby prolonging systemic circulation and improving delivery efficiency.

Exosomes are among the most widely studied biologically derived carriers. Typically measuring 30–150 nm in diameter, they consist of a lipid bilayer membrane encapsulating a broad range of endogenous bioactive cargos, including proteins, lipids, mRNAs, and microRNAs [38]. Their membrane composition, including surface proteins and glycosylation patterns, provides a degree of natural tropism toward specific recipient cells. In the setting of osteoporosis, this property can be exploited to deliver therapeutic molecules to osteoblasts, osteoclasts, or bone marrow mesenchymal stem cells (BMSCs), thereby modulating bone remodeling more precisely than non-specific systemic administration [39].

In addition to their carrier function, biologically derived vesicles may exert therapeutic effects through their intrinsic cargos. For example, vesicle-associated miRNAs or proteins can participate in the regulation of osteogenic differentiation, osteoclastogenesis, angiogenesis, and inflammation, all of which are critical processes in osteoporotic bone loss and repair. Engineering approaches, such as loading siRNA or miRNA mimics, modifying membrane surfaces with bone-targeting ligands, or hybridizing vesicles with synthetic nanomaterials, can further enhance cargo capacity, tissue specificity, and microenvironment responsiveness [40]. As a result, these systems are increasingly viewed not merely as passive carriers but as bioactive delivery platforms with dual therapeutic functions.

Representative studies have shown that engineered exosomes can effectively promote osteogenesis, inhibit osteoclast activity, and improve bone microarchitecture in osteoporotic animal models. Bone-targeted exosomes loaded with osteoregulatory nucleic acids have been reported to enhance osteogenic differentiation and angiogenesis while suppressing bone resorption. Similarly, miRNA-enriched extracellular vesicles have shown the capacity to increase bone mineral density and trabecular mass in vivo [41]. These findings collectively support the notion that biologically derived nanocarriers may offer unique advantages in coordinating drug delivery with endogenous signaling modulation.

Despite these encouraging developments, several barriers remain. The large-scale isolation, purification, quality control, and batch-to-batch consistency of biologically derived vesicles remain challenging. In addition, cargo heterogeneity, limited loading efficiency, and incomplete understanding of in vivo fate may constrain their translation. Even so, their excellent biological compatibility and multifunctional regulatory potential make them highly promising candidates for next-generation bone-targeted delivery systems.

Bone-targeted functionalized nanocarriers

Bone-targeted functionalized nanocarriers represent a particularly important direction in OP therapy because they are specifically designed to improve the selective accumulation of therapeutic agents within skeletal tissues. Their central principle is to endow nanocarriers with active targeting capability by modifying the carrier surface with bone-affinitive ligands, such as bisphosphonates, acidic oligopeptides, or other bone-targeting peptides [42]. These ligands can bind hydroxyapatite in bone matrix or preferentially recognize metabolically active bone surfaces, thereby increasing local drug exposure at disease sites while reducing off-target distribution and systemic toxicity.

Among the commonly used targeting moieties, bisphosphonates are the most established because of their strong affinity for calcium-rich mineral surfaces. Likewise, peptides rich in aspartic acid or serine residues, such as Asp-Ser-Ser (DSS), can bind exposed mineral components or remodeling-associated bone surfaces with high specificity [43]. By integrating these ligands into nanoparticles, micelles, liposomes, or hybrid carriers, researchers have developed a variety of bone-seeking platforms for the delivery of osteogenic drugs, anti-resorptive agents, anti-inflammatory molecules, and gene therapeutics [44].

An additional advantage of bone-targeted functionalized carriers is that they can be combined with stimuli-responsive release mechanisms. Because osteoporotic lesions and bone resorption lacunae are often associated with local acidity, elevated reactive oxygen species, or enzyme-rich microenvironments, nanocarriers responsive to pH, redox status, or enzymatic activity can be designed to release their cargos selectively after reaching the target site [45]. Such a combination of active targeting and local responsiveness may substantially enhance therapeutic precision. Moreover, these systems can co-deliver multiple agents that act through complementary pathways, thereby enabling simultaneous promotion of bone formation, inhibition of bone resorption, and modulation of the inflammatory or immune microenvironment [46].

At the mechanistic level, once accumulated in bone tissue, these carriers can efficiently deliver therapeutic cargos to osteoblast lineage cells or osteoclasts and thereby regulate key signaling pathways involved in bone remodeling, such as Wnt/β-catenin, BMP/Smads, RANKL/NFATc1, and NF-κB-related cascades [47–48]. In parallel, some systems may influence angiogenesis or local immune responses, further contributing to the restoration of a bone-favorable microenvironment. A growing body of preclinical evidence supports the potential of this strategy. For example, bone-targeted nanocoatings and nanoparticles capable of locally releasing osteogenic ions, selective estrogen receptor modulators, calcitonin, or bisphosphonates have shown favorable effects on trabecular microarchitecture, new bone formation, and cortical bone preservation in osteoporotic animal models [49–50]. These studies indicate that active bone targeting can effectively reduce the required systemic dose while enhancing local efficacy, which is highly relevant for chronic diseases such as osteoporosis .

Overall, bone-targeted functionalized nanocarriers are among the most promising platforms for precision OP therapy. By integrating active skeletal targeting with programmable drug release and multi-pathway intervention, they offer a rational approach to improving therapeutic selectivity and minimizing adverse effects. Future progress in this area will likely depend on optimizing ligand density, balancing targeting efficiency with systemic stability, and validating long-term safety and efficacy in clinically relevant models.

NDDSs for TCM in osteoporosis therapy

TCM, characterized by their multi-component, multi-target, and multi-pathway synergistic properties, have shown unique advantages in maintaining bone metabolic homeostasis by simultaneously promoting osteogenesis, inhibiting osteoclastogenesis, regulating inflammation and oxidative stress, and remodeling the bone immune microenvironment. Accordingly, they have long been used in the prevention and treatment of osteoporosis. However, conventional oral administration remains limited by gastrointestinal irritation, degradation in the digestive tract, poor water solubility, low membrane permeability, extensive first-pass metabolism, insufficient bioavailability, and inadequate bone-specific accumulation, all of which may compromise therapeutic efficacy and increase the risk of adverse effects or potential hepatorenal toxicity at high doses or during long-term use. NDDSs offer an effective strategy to address these challenges by improving the solubility, stability, and absorption of active compounds through encapsulation or self-assembly, while surface functionalization with bone-affinitive ligands or acidic oligopeptides further enables selective delivery and targeted or controlled release within the bone microenvironment. As shown in Fig. 2, NDDSs can enhance therapeutic efficacy while reducing systemic exposure and toxicity. Based on the material properties and application characteristics of nanocarriers, this chapter systematically summarizes the design strategies, representative studies, and mechanistic evidence of different carrier platforms for TCM-based anti-osteoporotic therapy, with particular emphasis on the translational value of bone-targeting and stimuli-responsive controlled-release technologies.

Fig. 2.

Nanoparticle formulations offer superior advantages compared to other dosage forms, and traditional Chinese medicine demonstrates greater efficacy than other drugs in the treatment of osteoporosis

Rhizoma drynariae and its extracts

Rhizoma Drynariae is a widely studied botanical in bone metabolism research due to its multi-component and multi-target properties [51–52]. Its main active constituents, such as total flavonoids and naringin (NG), have been shown to promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), enhance osteoblast proliferation, accelerate bone formation, and inhibit osteoclast activity, thereby reducing bone resorption [53]. To address poor water solubility and lack of targeting, Zhao et al. prepared Rhizoma Drynariae-derived nanovesicles (RDNVs) via differential centrifugation [54]. In vitro, RDNVs enhanced osteogenic differentiation of human BMSCs through estrogen receptor α targeting, and in ovariectomized mouse models, they exhibited bone tissue-specific accumulation and anti-osteoporotic effects.

NG, as a major monomer, demonstrates potent anti-inflammatory, antioxidant, and anti-apoptotic activities, acting through multiple signaling pathways to regulate bone metabolism [55]. Li et al. loaded NG into modified mesoporous bioactive glass nanoparticles, achieving prolonged release and promoting macrophage polarization toward the M2 phenotype, thereby modulating the local immune microenvironment to synergistically support bone homeostasis [56]. Similarly, Gera’s team developed naringin nanosuspensions (NG-NS), which enhanced osteogenic markers such as osteocalcin and alkaline phosphatase in MG-63 cells in vitro and improved bone mineral density in osteoporotic rat models, demonstrating effective in vivo anti-osteoporotic activity [57].

Epimedium and icariin

Epimedium contains icariin (ICA), a flavonoid with antioxidative and anti-inflammatory properties, which can restore the osteogenic activity of senescent BMSCs and suppress inflammatory senescent macrophages, thereby mitigating bone loss associated with aging [58–59]. Recent studies have demonstrated that ICA activates autophagy pathways, reduces senescence-associated secretory phenotype factors, and modulates TNF-α signaling, contributing to a favorable bone microenvironment [60].

Furthermore, Li et al. designed a nanoscale composite by self-assembling ICA with calcium ions (Ca²⁺) and zoledronic acid (ZOL), which is responsive to extracorporeal shock wave (ESW) stimulation. This system achieves controlled drug release within the bone marrow and simultaneously regulates osteoblast-adipocyte lineage commitment [61]. ICA inhibits PPARγ and FABP4 transcription, reducing adipogenesis and promoting osteogenesis, while Ca²⁺ and ESW enhance osteoblast activity and ZOL suppresses osteoclasts. In vivo, this targeted therapy significantly improved bone formation, mechanical strength, and elasticity, reducing osteoporotic fracture risk. Encapsulation of icariin within NDDSs not only improves its bioavailability and stability, but also enhances activation of osteogenic pathways such as Wnt/β-catenin and BMP/Smads signaling. Sustained intracellular delivery promotes Runx2 and Osterix expression, thereby improving osteoblast differentiation and bone formation.

Eucommia ulmoides and its extracts

Eucommia ulmoides bark and its active constituents, including polysaccharides and quercetin, have been demonstrated to promote osteogenesis through multiple molecular mechanisms [62]. Song et al. reported that Eucommia polysaccharides reduced osteoclast number and increased osteoblast number in dexamethasone-induced osteoporotic mice, enhancing cortical bone thickness. Mechanistically, modulation of gut microbiota composition and activation of ERK/JNK/Nrf2 and BMP-2/Smad signaling pathways were implicated in restoring oxidative balance and promoting osteogenic differentiation in MC3T3-E1 cells [63].

Quercetin has been shown to enhance alkaline phosphatase activity and mineralization under iron-overload conditions, reduce ROS production, and regulate apoptotic markers (caspase-3, BAX, Bcl-2), partly via Nrf2/HO-1 signaling [64]. A quercetin-loaded mesoporous bioactive glass nanoparticle system demonstrated sustained release and improved bone regeneration, while modulating the immune microenvironment via macrophage-mediated pathways and miR-21a-5p/NF-κB signaling [65]. Quercetin-based NDDSs can simultaneously promote osteogenic signaling and suppress Nrf2/HO-1-mediated inflammatory pathways, thereby improving bone remodeling balance and reducing inflammatory bone loss.

Curcuma longa and curcumin

Curcumin (Cur) is a hydrophobic polyphenolic compound extracted from Curcuma longa, with potent anti-inflammatory, antioxidant, and anti-apoptotic properties. Cur inhibits ROS-induced oxidative stress, prevents osteoblast apoptosis, and suppresses RANKL-mediated osteoclast differentiation, contributing to bone homeostasis maintenance [66]. In diabetic osteoporosis models, tFNA/Cur composites were developed to improve Cur bioavailability, protect its stability, and inhibit ferroptosis, thereby promoting osteogenic differentiation of BMSCs, reducing trabecular loss, and enhancing bone formation via Nrf2/GPX4 signaling [67].

Moreover, phosphatidylserine liposome-curcumin (PSLs-Cur) complexes have been shown to enhance bone metabolism markers, mechanical strength, and OPG expression in glucocorticoid-induced osteoporotic rats, highlighting their potential as an alternative therapeutic strategy [68]. Curcumin-loaded NDDSs exhibit enhanced regulation of oxidative stress-related pathways compared with free curcumin. Improved intracellular delivery can activate the Nrf2/GPX4 pathway more effectively, reduce ROS accumulation, and alleviate oxidative stress-induced osteoblast dysfunction.

Astragalus and its extracts

Astragalus is a classic herb for qi tonification. Modern pharmacological studies have demonstrated that its saponin components, astragaloside and astragaloside IV (AS/AS-IV), exhibit potential anti-osteoporotic activity. However, their clinical application is hindered by poor solubility, insufficient in vivo exposure, and weak bone-targeting capability. To address these challenges, researchers have developed bone-targeting nano-delivery systems for AS based on the “bone-targeting ligand–polymeric micelle” strategy. In the first approach, alendronate-modified mPEG-PLGA micelles were employed for oral delivery of AS (AS-AL-mPEG-PLGA) [69]. This system not only significantly improved pharmacokinetic profiles but also achieved quantitative enrichment in bone tissue: AS concentration in bone increased from approximately 1.95 µg/mL in the free drug group to about 112.78 µg/mL, accompanied by a higher area under the concentration–time curve (AUC), prolonged half-life (t₁/₂), and extended mean residence time (MRT), establishing a complete chain of evidence from “plasma exposure–bone distribution–efficacy.”

In the second approach, leveraging the chelating affinity of tetracycline (TC) for bone minerals, TC-grafted mPEG-PLGA micelles (TC-mPEG-PLGA/AS) were constructed [57]. These micelles exhibited a particle size of approximately 52 nm and significantly enhanced binding affinity to hydroxyapatite (HAp). Tissue distribution, micro-computed tomography (micro-CT), and histological analyses indicated improvements in bone microarchitecture and bone mineral density (BMD) in ovariectomized (OVX) osteoporotic rats, alongside increased AUC, MRT, and relative bioavailability (RBA) following intravenous administration.

Salvia miltiorrhiza and its extracts

Salvia miltiorrhiza is a representative herb for activating blood circulation and resolving stasis. Its phenolic acid component, tanshinol (Tan), has shown potential in bone metabolism-related diseases but suffers from susceptibility to oxidation, short half-life, and low bioavailability, limiting systemic administration. To overcome these limitations, a bone-targeting nano-delivery system (PSI-HAPs) was developed, comprising a hydroxyapatite (HAP) core coated with PSI/PEG-PSI/ALN-PEG-PSI for the injectable delivery of tanshinol [70]. Comparative evaluation of coating formulations in terms of encapsulation efficiency, drug loading, and in vivo distribution revealed that ALN-PEG-PSI-HAP (ALN-PEG/PSI = 1:20) exhibited superior bone distribution (sustained up to 120 h), lower accumulation in non-target tissues, and pH-sensitive drug release behavior. The system was prepared under mild aqueous conditions, avoiding ultrasonication and heating, thereby minimizing processing stress on the labile natural product.

Tripterygium wilfordii and its extracts

Celastrol, an active component derived from Tripterygium wilfordii, possesses anti-inflammatory and anti-resorptive potential, yet its poor water solubility and systemic toxicity pose significant risks. For the treatment of postmenopausal osteoporosis (PMOP), a bone-targeting mesoporous silica nanoparticle system modified with PEG-Asp₈ (C@MSN-P-A8) was developed to enable controlled release and bone targeting [71]. The particle size increased from approximately 120 nm (MSN) to approximately 174 nm after modification. Drug release behavior shifted from “nearly 60% release within 42 h” to “approximately 30% release within 42 h,” indicating markedly improved controlled release.

Celastrol, an active component derived from Tripterygium wilfordii, possesses anti-inflammatory and anti-resorptive potential, yet its poor water solubility and systemic toxicity pose significant risks. For the treatment of postmenopausal osteoporosis (PMOP), a bone-targeting mesoporous silica nanoparticle system modified with PEG-Asp₈ (C@MSN-P-A8) was developed to enable controlled release and bone targeting [71]. The particle size increased from approximately 120 nm (MSN) to approximately 174 nm after modification. Drug release behavior shifted from “nearly 60% release within 42 h” to “approximately 30% release within 42 h,” indicating markedly improved controlled release.

Mechanistic studies demonstrated that the system inhibited RANKL-induced osteoclast formation and function in vitro and downregulated the NF-κB/MAPK signaling pathway. In vivo, it improved BMD and trabecular microarchitecture and reduced osteoclast numbers in OVX rats, with fluorescence imaging confirming bone enrichment. Celastrol,-loaded NDDSs demonstrate enhanced inhibition of osteoclastogenesis through improved suppression of RANKL and NF-κB/MAPK signaling pathways, contributing to reduced bone resorption.

Herb-derived exosome-like nanovesicles

In recent years, exosome-like nanovesicles (EVLPs) directly isolated from medicinal herbs have emerged as a novel class of nano-delivery systems. These vesicles feature a lipid bilayer membrane encapsulating complex bioactive constituents, thereby functioning as both carriers and active agents [72].

First, Pueraria lobata-derived PELNs were shown to promote osteogenic differentiation and mineralization of human primary bone marrow mesenchymal stem cells (BMSCs) in vitro and exert protective effects in OVX osteoporotic rats [73]. Mechanistically, PELNs enhanced BMSC osteogenic function by modulating the gut microbiota-associated metabolite trimethylamine N-oxide (TMAO) and upregulating autophagy, establishing a regulatory axis of “nano-delivery–metabolite–autophagy–osteogenesis.”.

Second, Dioscorea opposita-derived YNVs increased BMD and promoted longitudinal bone growth in OVX osteoporotic mice, with the underlying mechanism linked to the BMP-2/p-p38/Runx2 signaling axis. Notably, the study indicated that the effects of YNVs were independent of traditionally recognized diosgenin. Following oral administration, YNVs were absorbed via the small intestine, and hepatorenal toxicity assessments supported their systemic safety [74].

Third, Morinda officinalis-derived MOEVLPs exhibited femoral targeting and favorable organ safety profiles in PMOP mice, with bone formation effects surpassing those of alendronate control. Mechanistically, MOEVLPs appeared to promote proliferation rather than direct osteogenic differentiation, thereby expanding the osteoprogenitor pool to facilitate subsequent bone formation, involving the MAPK-CREB/RSK1 pathway [75]. Ginsenoside-loaded nanocarriers may regulate osteogenesis and osteoimmune signaling simultaneously by improving intracellular delivery and modulating inflammatory cytokine secretion within the bone microenvironment.

Fourth, Panax ginseng-derived GDNs primarily function by inhibiting osteoclast differentiation. In bone marrow-derived macrophage (BMM) models, GDNs suppressed TRAP⁺ osteoclast formation and F-actin ring structure, and inhibited RANKL-associated signaling pathways including IκBα, JNK, and ERK. The study also highlighted that GDNs contain ginsenosides Rb1 and Rg1, and that the intact vesicles exhibited superior anti-osteoclastogenic activity compared to individual monomers or their combination. In a lipopolysaccharide (LPS)-induced bone resorption model, micro-CT and BMD parameters confirmed the bone-protective effects of GDNs [76].

Discussion

The integration of NDDSs with TCM represents a promising strategy to address the multifactorial nature of OP [13]. Unlike conventional pharmacotherapies that primarily target either bone resorption or bone formation, TCM-based nanomedicines exhibit a multi-dimensional regulatory capacity, simultaneously modulating osteogenesis, osteoclastogenesis, inflammation, oxidative stress, and osteoimmune interactions [77]. This systems-level intervention aligns more closely with the complex pathophysiology of OP and may offer advantages over single-target therapies [78].

From a mechanistic perspective, the therapeutic efficacy of NDDS-delivered TCM is not solely attributable to improved pharmacokinetics, but rather to the synergistic coupling of delivery efficiency and biological signaling modulation [13, 77]. For instance, flavonoid-based compounds such as icariin and naringin can activate osteogenic pathways (e.g., Wnt/β-catenin, BMP/Smads), while simultaneously suppressing osteoclast differentiation via inhibition of RANKL-mediated signaling [79–80]. When incorporated into nanocarriers, these effects are further amplified through enhanced bioavailability, sustained release, and improved accumulation at skeletal sites [81]. In addition, several nanoformulations have demonstrated the ability to regulate macrophage polarization toward the M2 phenotype, thereby establishing a favorable osteoimmune microenvironment that supports bone regeneration [82]. These findings suggest that NDDSs act not merely as passive carriers, but as functional platforms that reshape the bone remodeling niche.

Importantly, different classes of nanocarriers exhibit distinct advantages and limitations in the context of OP therapy [17]. Although a wide variety of NDDSs have demonstrated promising anti-osteoporotic effects in preclinical studies, their translational potential differs substantially depending on carrier composition, biological behavior, manufacturability, and clinical feasibility. Therefore, a critical comparison of different nanoplatforms is essential rather than merely cataloguing reported formulations.

Among currently available systems, organic nanocarriers, particularly PLGA-based nanoparticles, lipid nanoparticles, and liposomes, appear to possess the greatest near-term clinical translational potential. This is largely attributable to their favorable biocompatibility, controllable biodegradation, relatively mature manufacturing technologies, and previous regulatory approval in other biomedical applications. In particular, PLGA and lipid-based systems exhibit scalable production capability and comparatively well-established safety profiles, making them more suitable for long-term systemic administration in chronic diseases such as osteoporosis.

In contrast, inorganic nanocarriers, including mesoporous silica nanoparticles, graphene oxide, and metal-organic frameworks, provide superior structural stability and high drug-loading capacity. However, concerns remain regarding their long-term biodegradation, tissue accumulation, and potential nanotoxicity. These unresolved biosafety issues may limit their clinical translation despite excellent experimental efficacy. Similarly, biologically derived nanocarriers such as exosomes possess unique advantages in immune compatibility and endogenous signaling regulation, but their large-scale production, purification standardization, cargo heterogeneity, and storage stability remain major translational barriers.

Bone-targeted functionalized nanocarriers represent one of the most attractive future directions because they combine selective skeletal accumulation with controlled or stimuli-responsive drug release. Nevertheless, most current studies remain proof-of-concept investigations performed in small animal models. The targeting efficiency, in vivo stability, and reproducibility of these systems under clinically relevant conditions still require systematic validation.

Importantly, the majority of current evidence remains preclinical and presents several limitations. First, many studies rely predominantly on ovariectomized rodent models, which cannot fully replicate the complex pathological features and long-term progression of human osteoporosis. Second, therapeutic evaluations are often limited to bone mineral density and micro-CT parameters, while long-term fracture prevention, biomechanical outcomes, pharmacokinetics, immunogenicity, and chronic toxicity remain insufficiently investigated. Third, direct head-to-head comparisons between different nanocarrier platforms are largely lacking, making it difficult to determine which systems are truly superior for clinical application. Finally, batch-to-batch reproducibility, large-scale manufacturing, and regulatory standardization remain poorly addressed in most reports.

Therefore, future studies should place greater emphasis on comparative evaluation, translational feasibility, long-term biosafety, and clinically relevant therapeutic endpoints, rather than focusing solely on formulation novelty. Such efforts will be critical for advancing TCM-based NDDSs from experimental research toward real-world clinical application in osteoporosis therapy.

Future perspectives

Despite the encouraging preclinical outcomes of TCM-based NDDSs for osteoporosis therapy, several critical challenges continue to hinder their clinical translation. One major limitation is the lack of batch-to-batch reproducibility caused by variations in nanoparticle synthesis, drug loading efficiency, particle size distribution, and surface functionalization, particularly for complex biomimetic and herbal-derived nanoplatforms. Such inconsistencies may significantly affect therapeutic efficacy, pharmacokinetics, and biosafety profiles.

Long-term biosafety also remains insufficiently investigated. Although many nanocarriers exhibit favorable short-term biocompatibility in vitro and in small animal models, their long-term accumulation, metabolic fate, immunogenicity, and potential chronic toxicity in vivo remain unclear, especially for inorganic and multifunctional nanomaterials. Since osteoporosis requires prolonged treatment, comprehensive long-term safety evaluation is particularly important for future clinical application.

In addition, storage stability and large-scale manufacturing remain major translational barriers. Certain nanoformulations are susceptible to aggregation, premature drug leakage, structural instability, or loss of bioactivity during storage and transportation, which may compromise therapeutic consistency and shelf life. Therefore, future studies should place greater emphasis on formulation standardization, scalable manufacturing strategies, long-term stability optimization, and rigorous biosafety assessment to facilitate the clinical translation of TCM-based NDDSs for osteoporosis treatment.

Conclusions

In conclusion, TCM-based NDDSs offer a highly promising strategy for osteoporosis therapy by combining the multi-target pharmacological characteristics of traditional Chinese medicine with the bone-targeting, controlled-release, and microenvironment-responsive advantages of nanotechnology. Beyond improving the bioavailability and stability of TCM-derived compounds, NDDSs can actively regulate osteogenic, anti-resorptive, antioxidant, and osteoimmune signaling pathways, thereby contributing to restoration of bone remodeling homeostasis. Among current platforms, organic nanocarriers such as PLGA nanoparticles, liposomes, and lipid-based systems appear to possess the greatest near-term translational potential because of their favorable biocompatibility and scalable manufacturing feasibility, while biomimetic and multifunctional hybrid nanoplatforms may represent important future directions for precision osteoporosis therapy. Nevertheless, several major barriers, including limited long-term biosafety evaluation, insufficient batch reproducibility, storage instability, and the lack of clinically relevant validation, continue to hinder clinical translation. Future research should therefore focus on standardized manufacturing, long-term safety assessment, comparative evaluation of different nanoplatforms, and integration of emerging technologies such as AI-assisted formulation design, theranostic systems, and personalized nanomedicine to facilitate the development of clinically translatable nano-therapeutics for osteoporosis treatment.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Li-li Zhang and Yuxiang Zhou contributed equally to this work. Conceptualization and writing—original draf preparation, Li-li Zhang and Wei Xiong; Methodology and validation, Yuxiang Zhou; Software and formal analysis, Yifeng Yuan; Investigation and resources, Li-li Zhang, Xiaolin Shi and Wei Xiong; Data curation and supervision, Li-li Zhang; Writing—review and editing, Yifeng Yuan.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by “Pioneer” and “Leading Goose” R&D Program of Zhejiang (2025C02193, 2026C02A1083). National Comprehensive Reform Demonstration Zone for Traditional Chinese Medicine (Zhejiang Province) Science and Technology Co-construction Project (GZY-KJS-ZJ-2026-066).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval and consent to participate

Not applicable. This article is a review of previously published literature and does not involve any original experimental studies involving human participants or animals.

Consent for publication

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

Competing interests

The authors declare no competing interests.