Intrinsic Potency Research Articles

Improved composite network via bismuth iodide for efficient ice-nucleating application

The urgent demand for electricity requires more safe energy transportation. AgI-based weather modification agents are commonly employed to facilitate ice nucleation and remove the undesirable glaze icing to suppress the negative effects of natural disasters. However, the intrinsic nucleation potency of AgI strictly limits its further improvement. Here, a hexagonal BiI3 was added in AgI-based agents. The chemical interactions of BiI3 and precursors optimize the crystallization of the polymer composite, leading to an oriented composite network. In addition, BiI3 could alter the structure and morphology of the combustion products, therefore creating more possible heterogeneous nuclei sites. The resultant BiI3-modified AgI-based weather modification agent exhibits an ice nucleation ∼ 1014, which is nearly ten times higher than the sample without AgI-BiI3, leading to a 71.21 % enhancement of deicing efficiency compared to AgI sample. Our results indicate the effectiveness of BiI3 dopant to improve both nucleation and deicing performance for weather modification applications.

QM/MM Simulations of Afatinib-EGFR Addition: The Role of β-Dimethylaminomethyl Substitution.

Acrylamides are the most commonly used warheads of targeted covalent inhibitors (TCIs) directed at cysteines; however, the reaction mechanisms of acrylamides in proteins remain controversial, particularly for those involving protonated or unreactive cysteines. Using the combined semiempirical quantum mechanics (QM)/molecular mechanics (MM) free energy simulations, we investigated the reaction between afatinib, the first TCI drug for cancer treatment, and Cys797 in the EGFR kinase. Afatinib contains a β-dimethylaminomethyl (β-DMAM) substitution which has been shown to enhance the intrinsic reactivity and potency against EGFR for related inhibitors. Two hypothesized reaction mechanisms were tested. Our data suggest that Cys797 becomes deprotonated in the presence of afatinib, and the reaction proceeds via a classical Michael addition mechanism, with Asp800 stabilizing the ion-pair reactant state β-DMAM+/C797- and the transition state of the nucleophilic attack. Our work elucidates an important structure-activity relationship of acrylamides in proteins.

Structural and functional characterization of IgG- and non-IgG-based T-cell-engaging bispecific antibodies.

Bispecific T-cell-engaging antibodies are a growing class of therapeutics with numerous molecules being tested in clinical trials and, currently, seven of them have received market approval. They are structurally complex and function as adaptors to redirect the cytotoxicity of T cells to kill tumor cells. T-cell-engaging bispecific antibodies can be generally divided into two categories: IgG/IgG-like and non-IgG-like formats. Different formats may have different intrinsic potencies and physiochemical properties, and comprehensive studies are needed to gain a better understanding of how the differences in formats impact on structural and functional characteristics. In this study, we designed and generated bispecific T-cell-engaging antibodies with IgG-like (DVD-Ig) and non-IgG (BiTE) formats. Both target the same pair of antigens (EGFR and CD3) to minimize the possible influence of targets on functional characterization. We performed a side-by-side comparison to assess differences in the physiochemical and biological properties of these two bispecific T-cell-engaging antibodies using a variety of breast and ovarian cancer cell-based functional assays to delineate the structural-functional relationships and anti-tumor activities/potency. We found that the Fc portion of T-cell-engaging bispecific antibodies can significantly impact antigen binding activity, potency, and stability in addition to eliciting different mechanisms of action that contribute the killing of cancer cells.

Abstract 597: Vebreltinib: A novel brain-penetrating MET kinase inhibitor demonstrates the mechanism of action and pharmacological anti-tumor activity in diverse patient-derived MET-dysregulated tumor models at clinically relevant drug levels

Abstract Background: Dysregulation of the MET signaling pathway drives oncogenesis in many human cancers, the majority of which have not been addressed by a MET targeted therapy albeit the emerging therapies for MET exon 14 skipping (MET ex14) NSCLC. We have developed a novel highly selective MET kinase inhibitor vebreltinib (APL-101, PLB1001, bozitinib) to address unmet medical need. Vebreltinib is being jointly investigated in ongoing pivotal Phase 2 and 2/3 studies in MET-dysregulated NSCLC, primary CNS cancers and basket solid tumors in China (as PLB-1001) and globally ex-China (as APL-101). The Phase 1 portion of both studies have been concluded with the same RP2D (200 mg BID by oral administration). Vebreltinib demonstrated blood-brain barrier permeability in PLB-1001 Phase 1 glioblastoma study as previously reported. Methods: MET enzyme kinetics and vebreltinib intrinsic potency were studied by a radiometric MET kinase assay. Selectivity was profiled by in vitro KINOME. Vebreltinib cellular activity on MET signaling and in vivo anti-tumor activity were assessed in tumor cell lines and patient-derived tumors (PDX) carrying MET alterations. Results: Vebreltinib is an ATP-competitive inhibitor with Ki of approximately 2.2 nM for recombinant MET kinase and inhibited the native form of activated MET with 0.52 nM IC50. Vebreltinib demonstrated exquisite selectivity in KINOMEscan selectivity panel. Vebreltinib inhibited HGF-dependent and -independent MET signaling in KP4 tumor cell lines with nanomolar concentrations. Vebreltinib inhibited IL-3 independent Ba/F3 cell lines carrying exogenous MET ex14 or with secondary mutations induced by other MET TKIs. Vebreltinib inhibited MKN45 gastric tumor xenograft in vivo with ED90 of 6 mg/kg PO/QD. Furthermore, Vebreltinib demonstrated strong anti-tumor activity in a variety of PDX tumor types carrying MET ex14, MET fusions, and MET amplification. In these preclinical studies, the total and unbound vebreltinib plasma concentration observed at steady state trough of RP2D was used as a clinically relevant drug level to interpret Vebreltinib efficacy in blocking oncogenic MET signaling, proliferation of Ba/F3 cell lines with a broad spectrum of MET mutations and in vivo tumor growth in PDXs carrying diverse MET alterations. We demonstrated the rationale for Vebreltinib to be an efficacious single-agent MET inhibitor in treating tumors carrying MET driver alterations beyond MET ex14 NSCLC. Conclusion: Vebreltinib is a novel potent MET kinase inhibitor showing promising preclinical activity against PDXs from diverse organs sites and genomic alterations such as MET ex14, MET fusion, MET amplification, or HGF over-expression at clinically relevant drug levels, providing proof-of-concepts for continued clinical development. Citation Format: Xiaoling Zhang, Elaine Liu, Yan Song, Peony Yu, Sanjeev Redkar, Guo-Liang Yu. Vebreltinib: A novel brain-penetrating MET kinase inhibitor demonstrates the mechanism of action and pharmacological anti-tumor activity in diverse patient-derived MET-dysregulated tumor models at clinically relevant drug levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 597.

Design and synthesis of fluorine aromatic scaffolds containing drugs approved by the US FDA from 2002 to 2022

There are totally 93 fluorine aromatic scaffolds containing drugs approved by U.S. Food and Drug Administration from 2002 to 2022. The proportion of drugs containing fluorinated aromatic skeleton in approved drugs is increasing in recent ten years, which indicates the unique and important attributes of the fluorine atom. The introduction of fluorinated fragments into molecules can influence structure conformation, intrinsic potency and selectivity and pharmacokinetic properties productively. Additionally, 18F has been applied as a significant and useful positron emission tomography isotope for in vivo imaging technology. This review is mainly concentrated on the application and synthesis methods of 93 fluorine aromatic scaffolds containing drugs approved by the US FDA from 2002 to 2022. We hoped that this deep insight perspective into the synthetic methods for the delivery of these fluorine aromatic scaffolds containing drugs could offer practical and creative inspirations for the application and development of fluorine atom in new drug discovery.

Soft nanoparticles as antimicrobial agents and carriers of microbiocides for enhanced inhibition activity.

Antibiotic resistance continues to pose significant health challenges. Considering severe limitations in the discovery and supply of new antibiotics, there is an unmet need to design alternative and more effective strategies for addressing this global issue. Use of polymeric nanoparticles with cationic shell surfaces offers a highly promising approach to coupling their inherent bactericidal action with sustained delivery of small lipophilic microbicides. We have utilized this platform for assembling multi-tasking soft core-shell nanoparticles from star polymers with the desired asymmetric arm composition. These stable nanoparticles with low critical micelle concentration imparted intrinsic antimicrobial potency due to high positive charge density in the corona, as well as the loading of active biocidal agents (such as curcumin and terbinafine) for potential dual and coadjuvant inhibition. This strategic combination allows for both immediate (direct contact) and extended (drug delivery) antibacterial activities for better therapeutic efficacy. Micellar nanoparticles with and without therapeutic cargo were highly efficient against both Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis), representative Gram-negative and Gram-positive bacteria, respectively. Interestingly, we observed bacteria- and concentration-dependent effects, in which higher concentrations of charged nanoparticles were more effective against E. coli, whereas B. subtilis was inhibited only at lower concentrations. This work highlights a valuable platform to achieve combination therapy through nanoparticles with charged coronas and delivery of potent therapeutics to overcome antimicrobial resistance.

Microwave synthesis of Chitosan-stabilized selenium nanoparticles: Intrinsic oxidant scavenging capabilities, hemocompatibility, anticancer, and antibacterial potency

Chitosan-stabilized selenium nanoparticles (Ch-St-SeNPs) were produced using Chitosan (Ch) in conjunction with microwave technology. Based on the morphological analysis, it was determined that the Ch-St-SeNPs were spherical and had sizes that varied between 8.0 and 17.0 nm. In addition, the DPPH radical scavenging test was conducted to evaluate the antioxidant effectiveness. The results showed that the green nanoparticle, prepared at 100.0 mg/mL, exhibited the highest scavenging capacity (297.1 ± 10.2 mg g−1). The concentrations of Ch-St-SeNPs reach 500 mg/ml, and the in-vitro cell viability of Ch-St-SeNPs via human breast cancer MCF-7 cell lines will decrease to 41.2 ± 3.1 % within a day of exposure. The evaluation of Ch-St-SeNPs included an analysis of their hemolytic strength, which was found to be significant. According to the findings, Ch-St-SeNPs exhibited excellent results, with no noticeable effect on RBCs and a considerably lower toxicity rate (7.2 %) compared to Triton-X-100, which showed a toxicity rate of 98.1 %. The effectiveness of Ch-St-SeNPs was evaluated by testing its antibacterial properties against various types of bacteria, including Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), and Bacillus subtilis (B. subtilis). Results showed thatCh-St-SeNPs had a more significant impact on E. coli with a ZOI of 23.2 ± 1.3 mm compared to the standard antibiotic, which only had a ZOI of 15.0 ± 0.7 mm. According to prior research, Ch-St-SeNPs have potential applications in healthcare due to their ability as anticancer, antioxidants, and impact bacteria. In addition, the compatibility of human red blood cells is also a factor to consider.

In Silico Investigation of the Clinical Translatability of Competitive Clearance Glucose-Responsive Insulins.

The glucose-responsive insulin (GRI) MK-2640 from Merck was a pioneer in its class to enter the clinical stage, having demonstrated promising responsiveness in in vitro and preclinical studies via a novel competitive clearance mechanism (CCM). The smaller pharmacokinetic response in humans motivates the development of new predictive, computational tools that can improve the design of therapeutics such as GRIs. Herein, we develop and use a new computational model, IM3PACT, based on the intersection of human and animal model glucoregulatory systems, to investigate the clinical translatability of CCM GRIs based on existing preclinical and clinical data of MK-2640 and regular human insulin (RHI). Simulated multi-glycemic clamps not only validated the earlier hypothesis of insufficient glucose-responsive clearance capacity in humans but also uncovered an equally important mismatch between the in vivo competitiveness profile and the physiological glycemic range, which was not observed in animals. Removing the inter-species gap increases the glucose-dependent GRI clearance from 13.0% to beyond 20% for humans and up to 33.3% when both factors were corrected. The intrinsic clearance rate, potency, and distribution volume did not apparently compromise the translation. The analysis also confirms a responsive pharmacokinetics local to the liver. By scanning a large design space for CCM GRIs, we found that the mannose receptor physiology in humans remains limiting even for the most optimally designed candidate. Overall, we show that this computational approach is able to extract quantitative and mechanistic information of value from a posteriori analysis of preclinical and clinical data to assist future therapeutic discovery and development.

WHAM-FTOXβ – An aquatic toxicity model based on intrinsic metal toxic potency and intrinsic species sensitivity

We developed a model that quantifies aquatic cationic toxicity by a combination of the intrinsic toxicities of metals and protons and the intrinsic sensitivities of the test species. It is based on the WHAM-FTOX model, which combines the calculated binding of cations by the organism with toxicity coefficients (αH, αM) to estimate the variable FTOX, a measure of toxic effect; the key parameter αM,max (applying at infinite time) depends upon both the metal and the test species. In our new model, WHAM-FTOXβ, values of αM,max are given by the product αM* × β, where αM* has a single value for each metal, and β a single value for each species. To parameterise WHAM-FTOXβ, we assembled a set of 2182 estimates of αM,max obtained by applying the basic model to laboratory toxicity data for 76 different test species, covering 15 different metals, and including results for metal mixtures. Then we fitted the log10αM,max values with αM* and β values (a total of 91 parameters). The resulting model accounted for 72% of the variance in log10αM,max. The values of αM* increased markedly as the chemical character of the metal changed from hard (average αM* = 4.4) to intermediate (average αM* = 25) to soft (average αM* = 560). The values of log10β were normally distributed, with a 5–95 percentile range of -0.73 to +0.56, corresponding to β values of 0.18 to 3.62. The WHAM-FTOXβ model entails the assumption that test species exhibit common relative sensitivity, i.e. the ratio αM,max / αM* is constant across all metals. This was tested with data from studies in which the toxic responses of a single organism towards two or more metals had been measured (179 examples for the most-tested metals Ni, Cu, Zn, Ag, Cd, Pb), and statistically-significant (p < 0.003) results were obtained.

One-pot microwave synthesis of chitosan-stabilized silver nanoparticles entrapped polyethylene oxide nanofibers, with their intrinsic antibacterial and antioxidant potency for wound healing

Different physical and chemical techniques could be used to prepare chitosan/Silver nanoparticle (CHS/AgNPs) nanocomposite. The microwave heating reactor was rationally adopted as a benign tool for preparing CHS/AgNPs owing to less energy consumption and shorter time required for completing the nucleation and growth particles. UV–Vis, FTIR, and XRD, provided conclusive evidence of the AgNPs creation, while TEM micrographs elucidated that the size was spherical (20 nm). CHS/AgNPs were embedded in polyethylene oxide (PEO) nanofiber via electrospinning, and their biological properties, cytotoxicity evaluation, antioxidant, and antibacterial activity assays were investigated. The generated nanofibers have mean diameters of 130.9 ± 9.5, 168.7 ± 18.8, and 186.8 ± 8.19 nm for PEO, PEO/ CHS, and PEO/ CHS (AgNPs), respectively. Because of the tiny AgNPs particle size loaded in PEO/CHS (AgNPs) fabricated nanofiber, good antibacterial activity with ZOI against E. coli was 51.2 ± 3.2, and S. aureus was 47.2 ± 2.1 for PEO/ CHS (AgNPs) nanofibers. Non-toxicity was observed against Human Skin Fibroblast and Keratinocytes cell lines (>93.5 %), which justifies its great antibacterial potential to remove or prevent infection in wounds with fewer adverse effects.

The CuO and AgO co-modified ZnO nanocomposites for promoting wound healing in Staphylococcus aureus infection.

Bacterial has become a common pathogen of humans owing to their drug-resistant effects and evasion of the host immune system, with their ability to form biofilm and induce severe infections, a condition which has become a primary public health concern globally. Herein, we report on CuO@AgO/ZnO NPs antibacterial activity enhanced by near-infrared (NIR) light which was effective in the elimination of Staphylococcus aureus and the Pseudomonas aeruginosa. The CuO@AgO/ZnO NPs under NIR significantly eradicated S.aureus and its biofilm and P.aeruginosa in vitro, and subsequently exhibited such phenomenon in vivo, eliminating bacteria and healing wound. This demonstrated the combined intrinsic antibacterial potency of the Cu and Ag components of the CuO@AgO/ZnO NPs was enhanced tremendously to achieve such outcomes in vitro and in vivo. Considering the above advantages and facile preparation methods, the CuO@AgO/ZnO NPs synthesized in this work may prove as an important antibacterial agent in bacterial-related infection therapeutics and for biomedical-related purposes.

Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates.

Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.

“Liberty or Death!”

“Liberty or Death!”

Automated hierarchical screening of refractory multicomponent alloys with high intrinsic ductility and surface passivation potency

Automated hierarchical screening of refractory multicomponent alloys with high intrinsic ductility and surface passivation potency

Structural Basis of a Novel Agonistic Anti-OX40 Antibody.

Agonistic antibodies targeting co-stimulating receptor OX40 on T cells are considered as important as (or complementary to) the immune checkpoint blockers in cancer treatment. However, none of these agonistic antibodies have reached the late stage of clinical development partially due to the lack of intrinsic potency with the correlation between binding epitope and activity of the antibody not well understood. Here, we identified a novel anti-OX40 agonistic antibody DF004, which stimulated the proliferation of human CD4+ T cells in vitro and inhibited tumor growth in a mouse model. Our crystallography structural studies showed that DF004 binds to the CRD2 region of OX40 while RG7888, an OX40 agonist antibody developed by Roche, binds to CRD3 of OX40 to the diametrically opposite position of DF004. This suggests that the agonistic activities of the antibodies are not necessarily epitope dependent. As their agonistic activities critically depend on clustering or cross-linking, our structural modeling indicates that the agonistic activity requires the optimal positioning of three Fc receptor/antibody/OX40 complexes on the cell membrane to facilitate the formation of one intracellular hexameric TRAF complex for downstream signal transduction, which is relatively inefficient. This may explain the lack of sufficient potency of these OX40 antibodies in a therapeutic setting and sheds light on the development of cross-linking-independent agonistic antibodies.

Nickel: Intrinsic Skin Sensitization Potency and Relation to Prevalence of Contact Allergy.

Nickel: Intrinsic Skin Sensitization Potency and Relation to Prevalence of Contact Allergy.

Selective depletion of a CD64-expressing phagocyte subset mediates protection against toxic kidney injury and failure

Dendritic cells (DC), macrophages, and monocytes, collectively known as mononuclear phagocytes (MPs), critically control tissue homeostasis and immune defense. However, there is a paucity of models allowing to selectively manipulate subsets of these cells in specific tissues. The steady-state adult kidney contains four MP subsets with Clec9a-expression history that include the main conventional DC1 (cDC1) and cDC2 subtypes as well as two subsets marked by CD64 but varying levels of F4/80. How each of these MP subsets contributes to the different phases of acute kidney injury and repair is unknown. We created a mouse model with a Cre-inducible lox-STOP-lox-diphtheria toxin receptor cassette under control of the endogenous CD64 locus that allows for diphtheria toxin-mediated depletion of CD64-expressing MPs without affecting cDC1, cDC2, or other leukocytes in the kidney. Combined with specific depletion of cDC1 and cDC2, we revisited the role of MPs in cisplatin-induced kidney injury. We found that the intrinsic potency reported for CD11c+ cells to limit cisplatin toxicity is specifically attributed to CD64+ MPs, while cDC1 and cDC2 were dispensable. Thus, we report a mouse model allowing for selective depletion of a specific subset of renal MPs. Our findings in cisplatin-induced injury underscore the value of dissecting the functions of individual MP subsets in kidney disease, which may enable therapeutic targeting of specific immune components in the absence of general immunosuppression.

Cause Clarification of Cysteine Oxidation by Active Species Generated during the Oxidation Process of Cinnamaldehyde and Impact on an In Chemico Alternative Method for Skin Sensitization Using a Nucleophilic Reagent Containing Cysteine.

Aldehydes comprise a major portion of skin sensitizers because they can react with both cysteine and lysine. Moreover, cinnamaldehyde (CA) is a typical moderate sensitizer and is often used in an alternative test method for skin sensitization. The amino acid derivative reactivity assay (ADRA) is an in chemico test method that evaluates the reactivity of cysteine derivatives (N-(2-(1-naphthyl)acetyl)-l-cysteine, NAC) and lysine derivatives with the test chemicals and uses CA as a proficiency substance. We found that NAC depletion for CA was only 10-20% when CA was used directly from the reagent bottle, although it increased to almost 100% when stored after being aliquoted from the reagent bottle. It was also found that this was due to the air oxidation of NAC itself rather than the reaction of NAC with CA, indicating that this result simply shows an increase in apparent reactivity. Aldehydes are known to produce active species, such as radicals, during air oxidation. Therefore, we investigated whether radicals were generated under storage conditions using the radical scavenger OH-TEMPO. LC/MS/MS analysis revealed that CA and OH-TEMPO complexes were produced during the air oxidation of CA. In the results of five aldehydes, similar to CA, active species were not generated as significantly as CA. Collectively, during the evaluation of the aldehydes, it can be seen that careful measures need to be taken to prevent the aldehydes from oxidizing during storage, indicating that assessment without preventing air oxidation carries an increased risk of overestimation compared with the intrinsic skin sensitization potency.

Screening of generalized stacking fault energies, surface energies and intrinsic ductile potency of refractory multicomponent alloys

Body-centered cubic (bcc) refractory multicomponent alloys are of great interest due to their remarkable strength at high temperatures. Optimizing the chemical compositions of these alloys to achieve a combination of high strength and room-temperature ductility remains challenging. Systematic predictions of these correlated properties across a vast compositional space would speed the alloy discover process. In the present work, we performed first-principles calculations with the special quasi-random structure (SQS) method to predict the unstable stacking fault energy (γusf) of the (11¯0)[111] slip system and the (11¯0)-plane surface energy (γsurf) for 106 individual binary, ternary and quaternary bcc solid-solution alloys with constituent elements among Ti, Zr, Hf, V, Nb, Ta, Mo, W, Re and Ru. Moreover, with the first-principles data and a set of physics-informed descriptors, we developed surrogate models based on statistical regression to accurately and efficiently predict γusf and γsurf for refractory multicomponent alloys in the 10-element compositional space. Building upon binary and ternary data, the surrogate models show outstanding predictive capability in the high-order multicomponent systems. The ratio between γsurf and γusf can be used to populate a model of intrinsic ductility based on the Rice model of crack-tip deformation. Therefore, using the surrogate models, we performed a systematic screening of γusf, γsurf and their ratio over 112,378 alloy compositions to search for alloy candidates that may have enhanced strength-ductility synergies. Search results were also validated by additional first-principles calculations.

A novel vertical aligned mesoporous silica coated nanohydroxyapatite particle as efficient dexamethasone carrier for potential application in osteogenesis

Bone defect is a common problem and inducing osteoblasts differentiation is the key process for the regenerative repair. Recently, the mesoporous silica (MS) coated nanohydroxyapatite (nHA) particles (nHA-MS) has shown enhanced intrinsic potency for bone regeneration, whereas whether the osteogenesis potency can be further enhanced after drug delivery has not been investigated. In this study, the nHA-MS was fabricated by a novel biphase stratification growth way. The cytotoxicity in MC3T3-E1 was validated by MTT assay, apoptosis analysis and cell cycle examination. The cell uptake was observed by confocal laser scanning microscope and transmission electron microscope respectively. After adsorption with dexamethasone (DEX), the osteogenic differentiation was determined both in vitro and in vivo. The synthesized nHA-MS showed a core–shell structure that the nanorod-like nHA was coated by a porous MS shell (∼5 nm pores diameter, ∼50 nm thickness). A dose-dependent cytotoxicity was observed and below 10 µg ml−1 was a safe concentration. The nHA-MS also showed efficient cell uptake efficiency and more efficient in DEX loading and release. After DEX adsorption, the nanoparticles exhibited enhanced osteogenic induction in MC3T3-E1 and rat calvarial bone defect regeneration. In conclusion, the nHA-MS is a favorable platform for drug delivery to obtain more enhanced osteogenesis capabilities.