Icariin, a phytoestrogen, exerts rapid estrogenic actions through crosstalk of estrogen receptors in osteoblasts.

Icariin, a flavonoid glycoside derived from Epimedium brevicornum Maxim, exerts bone protective effects via estrogen receptors (ERs). This study aimed to investigate the role of ER-α66, ER-α36, and GPER in bone metabolism in osteoblasts following treatment with icariin. Human osteoblastic MG-63 cells and osteoblast-specific ER-α66 knockout mice were employed. The ERs crosstalk in the estrogenic action of icariin was evaluated in ER-α66-negative human embryonic kidney HEK293 cells. Icariin, like E2, regulated ER-α36 and GPER protein expression in osteoblasts by downregulating them and upregulating ER-α66. ER-α36 and GPER suppressed the actions of icariin and E2 in bone metabolism. However, the in vivo administration of E2 (2 mg/kg/day) or icariin (300 mg/kg/day) restored bone conditions in KO osteoblasts. ER-α36 and GPER expression increased significantly and rapidly activated and translocated in KO osteoblasts after treatment with E2 or icariin. ER-α36 overexpression in KO osteoblasts further promoted the OPG/RANKL ratio induced by E2 or icariin treatment. This study showed icariin and E2 elicit rapid estrogenic responses in bone through recruiting ER-α66, ER-α36, and GPER. Notably, in osteoblasts lacking ER-α66, ER-α36, and GPER mediate the estrogenic effects of icariin and E2, while in intact osteoblasts, ER-α36 and GPER act as negative regulators of ER-α66.

Identification of the Microbial Transformation Products of Secoisolariciresinol Using an Untargeted Metabolomics Approach and Evaluation of the Osteogenic Activities of the Metabolites.

Secoisolariciresinol (SECO) is one of the major lignans occurring in various grains, seeds, fruits, and vegetables. The gut microbiota plays an important role in the biotransformation of dietary lignans into enterolignans, which might exhibit more potent bioactivities than the precursor lignans. This study aimed to identify, synthesize, and evaluate the microbial metabolites of SECO and to develop efficient lead compounds from the metabolites for the treatment of osteoporosis. SECO was fermented with human gut microbiota in anaerobic or micro-aerobic environments at different time points. Samples derived from microbial transformation were analyzed using an untargeted metabolomics approach for metabolite identification. Nine metabolites were identified and synthesized. Their effects on cell viability, osteoblastic differentiation, and gene expression were examined. The results showed that five of the microbial metabolites exerted potential osteogenic effects similar to those of SECO or better. The results suggested that the enterolignans might account for the osteoporotic effects of SECO in vivo. Thus, the presence of the gut microbiota could offer a good way to form diverse enterolignans with bone-protective effects. The current study improves our understanding of the microbial transformation products of SECO and provides new approaches for new candidate identification in the treatment of osteoporosis.

Genistein Modified with 8-Prenyl Group Suppresses Osteoclast Activity Directly via Its Prototype but Not Metabolite by Gut Microbiota.

Postmenopausal osteoporosis is a significant threat to human health globally. Genistein, a soy-derived isoflavone, is regarded as a promising anti-osteoporosis drug with the effects of promoting osteoblastogenesis and suppressing osteoclastogenesis. However, its oral bioavailability (6.8%) is limited by water solubility, intestinal permeability, and biotransformation. Fortunately, 8-prenelylated genistein (8PG), a derivative of genistein found in Erythrina Variegate, presented excellent predicted oral bioavailability (51.64%) with an improved osteoblastogenesis effect, although its effects on osteoclastogenesis and intestinal biotransformation were still unclear. In this study, an in vitro microbial transformation platform and UPLC-QTOF/MS analysis method were developed to explore the functional metabolites of 8PG. RANKL-induced RAW264.7 cells were utilized to evaluate the effects of 8PG on osteoclastogenesis. Our results showed that genistein was transformed into dihydrogenistein and 5-hydroxy equol, while 8PG metabolites were undetectable under the same conditions. The 8PG (10-6 M) was more potent in inhibiting osteoclastogenesis than genistein (10-5 M) and it down-regulated NFATC1, cSRC, MMP-9 and Cathepsin K. It was concluded that 8-prenyl plays an important role in influencing the osteoclast activity and intestinal biotransformation of 8PG, which provides evidence supporting the further development of 8PG as a good anti-osteoporosis agent.

8-prenylgenistein exerts osteogenic effects via ER α and Wnt-dependent signaling pathway.

8-prenylgenistein (8PG) was previously reported to exert stronger osteogenic activity than genistein, a well-known soy phytoestrogen. However, the molecular mechanism underlying the actions of 8PG on osteoblasts was far from clear. In the present study, the osteogenic effects and mechanisms of 8PG and genistein were studied using human BMSC and murine pre-osteoblast MC3T3-E1 cells. Our results indicated that the stimulatory effects of 8PG and genistein on osteoblast differentiation were abolished by co-incubation with MPP (10-6 M, an ERα antagonist), but not PHTPP (10-6 M, an ERß antagonist). Molecular docking indicated that the binding mode of 8PG toward ERα was similar to that of genistein and therefore could not account for their differential osteogenic actions. In silico target profiling identified the involvement of glycogen synthase kinase-3ß (GSK-3ß), a key mediator of Wnt/ß-catenin pathway, in the actions of 8PG. However, instead of directly inhibiting GSK-3ß enzymatic activities, 8PG and genistein were found to induce GSK-3ß phosphorylation at Serine-9 in osteoblastic MC3T3-E1 cells. 8PG exerted more potent effects than genistein in stimulating expressions of LRP5, ß-catenin, Runx2, osteocalcin, alp, opg, major protein and gene markers involved in Wnt signaling pathway in MC3T3-E1 cells. Moreover, the inhibition of Wnt signaling by DKK1 could be restored by treatment with 8PG and genistein. However, 8PG, but not genistein, stimulated ERα-dependent ß-catenin protein expression in MC3T3-E1 cells. Furthermore, the increase in ALP activity, LRP5 and phospho-Akt/Akt expression by 8PG and genistein were abolished by co-treatment with LY294002 (10-5 M, a PI3K pathway inhibitor). Collectively, our results suggested that the osteogenic activities of 8PG was mediated by GSK-3ß phosphorylation through the induction of Wnt/ß-catenin and ERα-associated PI3K/Akt signaling.

A standardized extract of Danggui Buxue Tang decoction selectively exerts estrogenic activities distinctly from tamoxifen.

More and more menopausal women use Danggui Buxue Tang (DBT) for relieving their symptoms. Concerns for its safety have been raised as it contains phytoestrogen and acts via estrogen receptors (ERs). Our study aimed to determine whether DBT could selectively exert estrogenic activities and interact with tamoxifen in bone, brain, uterus, and breast by using ovariectomized (OVX) rats and ER-positive cells. In OVX rats, DBT induced a 31.4% increase in bone mineral density and restored the mRNA expression of dopamine biomarker in striatum, 3.32-fold for tyrosine hydrolase (p < .001) and 0.21-fold for dopamine transporter (p < .001), which was similar to tamoxifen; tamoxifen, but not DBT, increased uterus weight and Complement component 3 expression by more than twofold (p < .001); unlike tamoxifen, DBT induced mild proliferation in mammary gland. Two-way ANOVA indicated the interactions between them in OVX rats (p < .05) but DBT did not alter the responses to tamoxifen. DBT stimulated proliferation or differentiation and estrogen response element in MCF-7, MG-63, Ishikawa, and SHSY5Y cells and altered the effects of tamoxifen. In summary, DBT exerted estrogenic effects in tissue-selective manner, which was different from tamoxifen. DBT interacted with tamoxifen but did not significantly alter its effects in OVX rats.

Natural Products as Potential Bone Therapies.

Demands for natural products, in the form of botanicals, dietary supplements, and herbal medicine, for management of chronic diseases are increasing globally. Natural products might be an alternative for the management of bone health to meet the demands of a growing aging population. Different types of natural products, including Chinese herbal medicine decoctions, herbs, and isolated phytochemicals, have been demonstrated to exert bone protective effects. The most common types of bone protective bioactives are flavonoids, stilbene, triterpenoids, coumestans, lignans, and phenolic acid. The actions of natural products can be mediated by acting systemically on the hormonal axis or locally via their direct or indirect effects on osteogenesis, osteoclastogenesis, as well as adipogenesis. Furthermore, with the use of metabolomic and microbiome approaches to understand the actions of natural products, novel mechanisms that involve gut-brain-bone axis are also revealed. These studies provide evidence to support the use of natural products as bone therapeutics as well as identify new biological targets for novel drug development.

Positive relationship between consumption of specific fish type and n-3 PUFA in milk of Hong Kong lactating mothers.

Residents of Hong Kong have undergone a dietary transition from a traditional Chinese diet that is high in seafood to a more Western diet. This may have affected the nutritional composition of breast milk of Hong Kong mothers. The present study aims to investigate the relationship between the dietary pattern and the fatty acid profile of the breast milk of lactating women in Hong Kong. Seventy-three volunteering healthy Hong Kong lactating mothers participated in the study. Their dietary intakes were assessed by using a 3-d dietary record and FFQ. The mean n-3 fatty acid levels were approximately 0·4 % (EPA) and 0·9 % (DHA) of total fatty acids in the breast milk of lactating mothers who had exclusively breastfed their infants aged 2-6 months. Maternal dietary intakes of n-3 fatty acids were positively associated with their levels in the breast milk. The levels of maternal intakes of freshwater and saltwater fish, especially the consumption of salmon, croaker and mandarin, were significantly correlated with the content of DHA in breast milk. The present study is among the very few in the literature to determine the fatty acid profile of breast milk in Hong Kong populations and verify certain dietary factors that influence this profile. High levels of n-3 PUFA, especially DHA, were observed in the breast milk of Hong Kong lactating women. The findings may serve as a dietary reference for lactating mothers to optimise the fatty acid profile of their breast milk.

NMR Applications for Botanical Mixtures: The Use of HSQC Data to Determine Lignan Content in Sambucus williamsii.

Lignans found in the botanical extract of the Traditional Chinese Medicine Sambucus williamsii Hance exhibit protective effects on trabecular bone mass and mechanical strength of cortical bone of ovariectomized rats. A novel approach was adapted using HSQC NMR methods to estimate the total amount of these bioactives in a complex mixture. It was determined that lignans possessing the hydroxy- or oxybenzyl carbon signal were bioactive. These compounds were readily identified and assigned in a defined region of the 13C NMR spectrum at 80-90 ppm and calculated as 10-15% of the lignan-rich fraction of S. williamsii. Comparison of the peak heights of the oxybenzyl-substituted carbon resonance signals of the lignans in the botanical extract was made against those of a standard lignan pinoresinol. The application of this simple and reliable NMR method can be used to estimate amounts of related compounds and chemical families in complex mixtures or botanical extracts and offers measurable scientific evidence in quality processes. This is of particular importance for registration requirements of botanical drugs and in complex mixtures of botanical extracts.

A nanoencapsulation suspension biomimetic of milk structure for enhanced maternal and fetal absorptions of DHA to improve early brain development.

Docosahexaenoic acid (DHA) is one ω-3 fatty acid that is essential for the development and function of the brain. However, a large number of clinical trials found that the DHA supplementation showed no advantage on mental and motor skill development in term infants. A strategy based on DHA nanoencapsulation (nano FO) using an edible plant protein, zein, mimicking the milk structure is applied for enhanced maternal and fetal absorptions of DHA to improve early brain development. The nano FO achieved increased absorption in GI tract, enhanced delivery to the maternal, fetal, and offspring brains, and reduced fatty acid accumulation in the fetal liver. In the behavior assessments, the nano FO diet showed enhanced learning and memory improvement compared to the normal FO diet. It indicated that zein nanoencapsulation is with high potential for drug and nutrient deliveries to brain and through placenta to fetus with no toxicity concern.

Both Oleanolic Acid and a Mixture of Oleanolic and Ursolic Acids Mimic the Effects of Fructus ligustri lucidi on Bone Properties and Circulating 1,25-Dihydroxycholecalciferol in Ovariectomized Rats.

Background: Oleanolic acid (OA) and ursolic acid (UA) are major chemical constituents found in Fructus ligustri lucidi (FLL), a Chinese herb previously shown to increase bone properties and modulate calcium-vitamin D metabolism in rats. OA and UA have been reported to exert osteoprotective effects in vitro. Objective: The present study was designed to determine whether OA or OA + UA mimicked the effects of FLL on bone and calcium homeostasis using ovariectomized rats. Methods: Three-month-old ovariectomized Sprague-Dawley rats were stabilized for 2 mo and randomly assigned to 4 groups offered the same amount (15-17 g/d) of a control diet or experimental diets containing FLL (18.8 g/kg), OA (0.67 g/kg), or OA (0.67 g/kg) + UA (0.22 g/kg) for 6 wk. Serum was obtained for measurement of 1,25-dihydroxycholecalciferol [1,25(OH)2D3] and bones were collected for micro-CT analysis. Calcium balance was measured at weeks 1 and 6. A calcium kinetic study using 45Ca was conducted at week 6 and modeled using WinSAAM software. Results: Compared with the control group, rats fed the FLL-, OA-, and OA + UA-enriched diets had better bone properties and 51%, 31%, and 27% higher serum 1,25(OH)2D3 concentrations at week 6, respectively. These variables did not differ between the treatments. Calcium balance was not affected by diet at either week 1 or week 6. Kinetic modeling predicted that FLL and OA + UA diet-fed rats had 9% and 15% less endogenous excretion of calcium, respectively, compared with the control group. All 3 treatments resulted in a higher calcium mass of compartment 3 because of changes in transfer rate between compartments 2 and 3, and were positively associated with the serum 1,25(OH)2D3 concentration (R2 = 0.28; P < 0.01). Conclusion: Similar to FLL, OA and OA + UA increase bone properties, serum 1,25(OH)2D3 concentration, and calcium use in ovariectomized rats, suggesting their potential role in management of osteoporosis.

New secoiridoids from the fruits of Ligustrum lucidum.

Three new secoiridoids, nuezhenelenoliciside (1), isojaslanceoside B (2), 6'-O-trans-cinnamoyl-secologanoside (3), were isolated from the dried fruits of Ligustrum lucidum. Their structures were elucidated by comprehensive spectroscopic analysis. Among them, 1 featured a rare rearrangement product of secoiridoid, which underwent the cleavage of chemical bond between C-1 and O-2, and the reformation of a new iridoid ring between C-8 and O-2. In addition, all compounds were tested for their osteogenic activity on pre-osteoblastic MC3T3-E1 cells. As a result, 1 and 3 exhibited potent effects on promoting cell proliferation of pre-osteoblast cells.

A High-Saturated-Fat, High-Sucrose Diet Aggravates Bone Loss in Ovariectomized Female Rats.

BACKGROUND: Estrogen deficiency in women and high-saturated fat, high-sucrose (HFS) diets have both been recognized as risk factors for metabolic syndrome. Studies on the combined actions of these 2 detrimental factors on the bone in females are limited. OBJECTIVE: We sought to determine the interactive actions of estrogen deficiency and an HFS diet on bone properties and to investigate the underlying mechanisms. METHODS: Six-month-old Sprague Dawley sham or ovariectomized (OVX) rats were pair fed the same amount of either a low-saturated-fat, low-sucrose (LFS) diet (13% fat calories; 15% sucrose calories) or an HFS diet (42% fat calories; 30% sucrose calories) for 12 wk. Blood, liver, and bone were collected for correspondent parameters measurement. RESULTS: Ovariectomy decreased bone mineral density in the tibia head (TH) by 62% and the femoral end (FE) by 49% (P < 0.0001). The HFS diet aggravated bone loss in OVX rats by an additional 41% in the TH and 37% in the FE (P < 0.05). Bone loss in the HFS-OVX rats was accompanied by increased urinary deoxypyridinoline concentrations by 28% (P < 0.05). The HFS diet induced cathepsin K by 145% but reduced osteoprotegerin mRNA expression at the FE of the HFS-sham rats by 71% (P < 0.05). Ovariectomy significantly increased peroxisome proliferator-activated receptor γ mRNA expression by 136% and 170% at the FE of the LFS- and HFS-OVX rats, respectively (P < 0.05). The HFS diet aggravated ovariectomy-induced lipid deposition and oxidative stress (OS) in rat livers (P < 0.05). Trabecular bone mineral density at the FE was negatively correlated with rat liver malondialdehyde concentrations (R(2) = 0.39; P < 0.01). CONCLUSIONS: The detrimental actions of the HFS diet and ovariectomy on bone properties in rats occurred mainly in cancellous bones and were characterized by a high degree of bone resorption and alterations in OS.

Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis.

Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis. It has been the focus of target based drug discovery in recent years. We have identified two components in RD, Kushennol F and Sophoraflavanone G, that can potentially interact with Ctsk. Biological studies were performed to verify the effects of these compounds on Ctsk and its related bone resorption process, which include the use of in vitro fluorescence-based Ctsk enzyme assay, bone resorption pit formation assay, as well as Receptor Activator of Nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis using murine RAW264.7 cells. Finally, the binding mode and stability of these two compounds that interact with Ctsk were determined by molecular docking and dynamics methods. The results showed that the in silico target fishing method could successfully identify two components from RD that show inhibitory effects on the bone resorption process related to protease Ctsk.

Two new phenylpropanoids and one new sesquiterpenoid from the bioactive fraction of Sambucus williamsii.

Two new phenylpropanoids, samwirin (1) and samwiphenol (2), and a new sesquiterpenoid, 2ß,4ß,10α-trihydroxy-1αH,5ßH-guaia-6-ene (3), together with six known compounds were isolated from the bioactive fraction of Sambucus williamsii Hance. Their structures including the absolute configurations were characterized on the basis of extensive 1D, 2D-NMR, MS, and CD spectral data. In vitro proliferation effects of all compounds on osteoblast-like UMR 106 cells were examined. Compounds 1, 4-9 significantly promoted cell proliferation. Compounds 5, 6, and 8 increased osteoblastic cell numbers separately by 24.3%, 25.2%, and 29.1% at 10(-10) M, 10(-10) M, and 10(-8) M, respectively.

Effects of angiotensin-converting enzyme inhibitor, captopril, on bone of mice with streptozotocin-induced type 1 diabetes.

There are contradictory results about the effect of angiotensin-converting enzyme inhibitors (ACEIs) on bone. This study was performed to address the skeletal renin-angiotensin system (RAS) activity and the effects of the ACEI, captopril, on the bone of streptozotocin-induced type 1 diabetic mice. Histochemical assessment on bone paraffin sections was conducted by Safranin O staining and tartrate-resistant acid phosphatase staining. Micro-computed tomography was performed to analyze bone biological parameters. Gene and protein expression were determined by real-time polymerase chain reaction and immunoblotting, respectively. Type 1 diabetic mice displayed osteopenia phenotype and captopril treatment showed no osteoprotective effects in diabetic mice as shown by the reduction of bone mineral density, trabecular thickness and bone volume/total volume. The mRNA expression of ACE and renin receptor, and the protein expression of renin and angiotensin II were markedly up-regulated in the bone of vehicle-treated diabetic mice compared to those of non-diabetic mice, and these molecular changes of skeletal RAS components were effectively inhibited by treatment with captopril. However, treatment with captopril significantly elevated serum tartrate-resistant acid phosphatase 5b levels, reduced the ratio of osteoprotegerin/receptor activator of nuclear factor-κB ligand expression, increased carbonic anhydrase II mRNA expression and the number of matured osteoclasts and decreased transforming growth factor-ß and osteocalcin mRNA expression in the tibia compared to those of diabetic mice. The present study demonstrated that the use of the ACEI, captopril, has no beneficial effect on the skeletal biological properties of diabetic mice. However, this could be attributed, at least partially, to its suppression of osteogenesis and stimulation of osteoclastogenesis, even though it could effectively inhibit high activity of local RAS in the bone of diabetic mice.

A systematic review on biological activities of prenylated flavonoids.

CONTEXT: Prenylated flavonoids are a unique class of naturally occurring flavonoids that exist especially for the plant's self-defensive strategy. This special class of flavonoids increases the bioactivities of their backbone flavonoids with non-prenylation; therefore, prenylated flavonoids have more potential to be developed and utilized. OBJECTIVE: The number, position and type of the prenyl group on the flavonoids backbone structure may have close relationships with the bioactivities of flavonoids. METHODS: PubMed and WEB OF KNOWLEDGE® were used to search articles published in English between 1 January 2002 and 31 December 2012, which discuss the structure-activity relationship between prenylated flavonoids and their bioactivities. RESULTS: It is proposed that the prenyl-moiety makes the backbone compound more lipophilic, which leads to its high affinity with cell membranes. The prenylation brings the flavonoids with enhancement of antibacterial, anti-inflammatory, antioxidant, cytotoxicity, larvicidal as well as estrogenic activities. However, it is reported that the prenyl-moiety decreases the bioavailability and plasma absorption of prenylated flavonoids. CONCLUSION: The prenyl group affects the bioactivities of flavonoids in certain ways, while the action mechanisms and the structure-activity relationship as well as more in vivo studies even clinical validation trials need to be further investigated.

Chinese herbal medicine for bone health.

CONTEXT: Chinese herbal medicine (CHM) has been widely used in clinical practice to treat bone disease for thousands of years. They are cost-effective with fewer side effects and are more suitable for long-term use compared with chemically synthesized medicines. OBJECTIVE: Chinese herbal formula prescribed among the CHMs is safe, and it is an alternative medicine for bone-related diseases such as osteoporosis. METHODS: Science Direct and Google Scholar were used to search articles published. The input key words were CHM, osteoporosis, Chinese herbal formula, traditional Chinese medicine, single herb, multiple-herbs, and bone health. CHMs (single herb and formula) lacking sufficient proof and evidence in the literature were excluded and only those with high citation were retained. RESULTS: A brief review was summarized to indicate the application and the potential mechanism of single herb formula and multi-herb formula in treating the common bone-related diseases such as inflammation, fracture, osteopenia, and osteoporosis. CONCLUSION: In order to ensure safety and efficacy of all these CHMs, the prescriptions with single herb and multi-component formula must be verified and ensured by reliable pharmacological and toxicological methods. Much more effort needs to be done for studying the standardization, safety evaluation, and mechanism exploration of herb formula as well as confirming the compatibility of these herbs which make one.

[Lignans isolated from stems of Sambucus williamsii and their proliferation effects on UMR106 cells].

The present study aims to investigate the lignan constituents from Sambucus williamsii and their proliferation effects on osteoblast-like UMR106 cells. Seven compounds were isolated and purified by macroporous resin D101, silica gel, Sephadex LH-20, Toyopearl HW-40, ODS column chromatographies and Preparative HPLC(C-18). Their structures were elucidated by spectroscopic methods as threo-guaiacylglycerol-beta-0-4'-conifery ether (1), lirioresinol A (2), 1-hydroxypinoresinol (3), 5-methoxybalanophonin (4), balanophonin (5), 5-methoxy-trans-dihydrodehydrodiconiferyl alcohol (6), and p-hydroxybenzaldehyde (7). Compounds 3-7 were obtained from this genus for the first time. The proliferation effects of all isolated compounds on osteoblast-like UMR106 cells were determined. Compounds 1-7 (1 x 10(-12)-1 x 10(-7) mol x L(-1)) increased UMR106 cell proliferation to some extent.

Nanozymes for Treating Ocular Diseases.

Nanozymes, characterized by their nanoscale size and enzyme-like catalytic activities, exhibit diverse therapeutic potentials, including anti-oxidative, anti-inflammatory, anti-microbial, and anti-angiogenic effects. These properties make them highly valuable in nanomedicine, particularly ocular therapy, bypassing the need for systemic delivery. Nanozymes show significant promise in tackling multi-factored ocular diseases, particularly those influenced by oxidation and inflammation, like dry eye disease, and age-related macular degeneration. Their small size, coupled with their ease of modification and integration into soft materials, facilitates the effective penetration of ocular barriers, thereby enabling targeted or prolonged therapy within the eye. This review is dedicated to exploring ocular diseases that are intricately linked to oxidation and inflammation, shedding light on the role of nanozymes in managing these conditions. Additionally, recent studies elucidating advanced applications of nanozymes in ocular therapeutics, along with their integration with soft materials for disease management, are discussed. Finally, this review outlines directions for future investigations aimed at bridging the gap between nanozyme research and clinical applications.

Metal-Drug Coordination Nanoparticles and Hydrogels for Enhanced Delivery.

Drug delivery is a key component of nanomedicine, and conventional delivery relies on the adsorption or encapsulation of drug molecules to a nanomaterial. Many delivery vehicles contain metal ions, such as metal-organic frameworks, metal oxides, transition metal dichalcogenides, MXene, and noble metal nanoparticles. These materials have a high metal content and pose potential long-term toxicity concerns leading to difficulties for clinical approval. In this review, recent developments are summarized in the use of drug molecules as ligands for metal coordination forming various nanomaterials and soft materials. In these cases, the drug-to-metal ratio is much higher than conventional adsorption-based strategies. The drug molecules are divided into small-molecule drugs, nucleic acids, and proteins. The formed hybrid materials mainly include nanoparticles and hydrogels, upon which targeting ligands can be grafted to improve efficacy and further decrease toxicity. The application of these materials for addressing cancer, viral infection, bacterial infection inflammatory bowel disease, and bone diseases is reviewed. In the end, some future directions are discussed from fundamental research, materials science, and medicine.