journal article·2026-01Open access

Application of nano-drug delivery systems in the treatment of bone diseases: Mechanisms, strategies and challenges

Guoyang Zhang, Weixuan Lin, Linghuan Guo, Yu Xiang, Luo Wang, Xiaoyu Yan

Materials & Design· Volume 261

Abstract

• Reviews the latest nano-drug delivery systems (NDDS) applications in skeletal diseases, focusing on disease-specific needs to overcome the limitations of drug treatment. • Offers a multi-dimensional practical reference for researchers, covering material selection, size regulation, modification, drug loading and release. • Constructs a systematic, practical handy book for NDDS in orthopedics, spanning basic design to clinical translation. • Outlooks multifunctional integration and Artificial Intelligence-assisted NDDS trends, guiding clinical translation breakthroughs. As a major class of diseases threatening human health and impairing quality of life, bone diseases present significant therapeutic challenges, including low drug bioavailability and inadequate targeting. Nano-drug delivery systems (NDDS) have emerged as a cutting-edge strategy, leveraging their unique advantages in enhancing local drug concentrations, enabling precise targeting, and facilitating intelligent drug release, with evolving material technologies needing systematic sorting for optimized design and application. Focusing on bone disease therapy, this review comprehensively covers the material selection of NDDS, preparation strategies, drug loading methods, and delivery mechanisms. It elaborates on the functional design strategies of NDDS tailored to address the specific needs of bone disease treatment, such as promoting bone formation, angiogenesis, neural regulation, inflammation inhibition, and anti-tumor effects. Additionally, this review analyzes the key challenges hindering the clinical translation of NDDS, while envisioning the transformative potential of intelligent design trends. Overall, this work serves not only as a systematic reference for the precise application and optimization of NDDS in bone disease therapy but also as a handy guide to help researchers organize existing research progress and support clinicians in exploring translational therapeutic strategies—effectively bridging academic research and clinical translation to serve both communities.
Source: openalex_inverted_index · Quality: baseline

Research context

OpenAlex topics: Bone Tissue Engineering Materials · Bone Metabolism and Diseases · Bone health and osteoporosis research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

References (100+)

Show source-provided references
1. The epidemiology of osteoporosis10.1093/bmb/ldaa005 ↗
2. Shevroja · Osteoporos. Int. · 2023 · 34 · 150110.1007/s00198-023-06817-4 ↗
3. Harvey · Osteoporos. Int. · 2017 · 28 · 44710.1007/s00198-016-3773-6 ↗
4. C. Cooper, T. Bardin, M.-L. Brandi, P. Cacoub, J. Caminis, R. Civitelli, M. Cutolo, W. Dere, J.-P. Devogelaer, A. Diez-Perez, T.A. Einhorn, P. Emonts, O. Ethgen, J.A. Kanis, J.-M. Kaufman, T.K. Kvien, W.F. Lems, E. McCloskey, P. Miossec, S. Reiter, J. Ringe, R. Rizzoli, K. Saag, J.-Y. Reginster, Balancing benefits and risks of glucocorticoids in rheumatic diseases and other inflammatory joint disorders: new insights from emerging data. An expert consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), Aging Clin. Exp. Res. 28 (2016) 1–16. https://doi.org/10.1007/s40520-015-0522-1.10.1007/s40520-015-0522-1 ↗
5. In situ preparation of alendronate-loaded ZIF-8 nanoparticles on electrospun nanofibers for accelerating early osteogenesis in osteoporosis10.1016/j.matdes.2022.110596 ↗
6. Role of oxidative stress and inflammation in doxorubicin-induced cardiotoxicity: a brief account10.3390/ijms25137477 ↗
7. Bench-to-bedside: feasibility of nano-engineered and drug-delivery biomaterials for bone-anchored implants and periodontal applications
8. Bone targeted nano-drug and nano-delivery10.1038/s41413-024-00356-2 ↗
9. Nano drug delivery systems: a promising approach to scar prevention and treatment10.1186/s12951-023-02037-4 ↗
10. Prospects for hypoxia-based drug delivery platforms for the elimination of advanced metastatic tumors: from 3D modeling to clinical concepts10.1016/j.jconrel.2022.12.009 ↗
11. Metal–organic framework-based smart stimuli-responsive drug delivery systems for cancer therapy: advances challenges, and future perspectives10.1186/s12951-025-03252-x ↗
12. Advanced bio-polymers for bone regeneration: harnessing anti-inflammatory, oxidative stress, and pro-angiogenic strategies10.1016/j.matdes.2025.114986 ↗
13. Bone tissue engineering via carbon-based nanomaterials10.1002/adhm.201901495 ↗
14. Novel inorganic nanomaterial-based therapy for bone tissue regeneration10.3390/nano11030789 ↗
15. Metal-based nano-delivery platform for treating bone disease and regeneration
16. Self‐healing biomaterials: the next generation is nano10.1002/wnan.1641 ↗
17. Polymeric nanocomposite hydrogel scaffolds in craniofacial bone regeneration: a comprehensive review10.3390/biom13020205 ↗
18. Recent trends in the application of widely used natural and synthetic polymer nanocomposites in bone tissue regeneration10.1016/j.msec.2020.110698 ↗
19. Periosteum and development of the tissue-engineered periosteum for guided bone regeneration
20. Near‐infrared carbon dots with antibacterial and osteogenic activities for sonodynamic therapy of infected bone defects10.1002/smll.202404900 ↗
21. Osteoporosis remission and new bone formation with mesoporous silica nanoparticles10.1002/advs.202101107 ↗
22. Piezoelectric heterojunctions as bacteria‐killing bone‐regenerative implants10.1002/adma.202570006 ↗
23. Nanoparticles to knockdown osteoporosis-related gene and promote osteogenic marker expression for osteoporosis treatment10.1021/acsnano.9b00241 ↗
24. Development of novel gene carrier using modified nano hydroxyapatite derived from equine bone for osteogenic differentiation of dental pulp stem cells
25. Puerarin@Chitosan composite for infected bone repair through mimicking the bio-functions of antimicrobial peptides
26. Magnetic aggregation‐induced bone‐targeting nanocarrier with effects of piezo1 activation and osteogenic–angiogenic coupling for osteoporotic bone repair10.1002/adma.202312081 ↗
27. Degradable nanohydroxyapatite-reinforced superglue for rapid bone fixation and promoted osteogenesis10.1021/acsnano.4c01214 ↗
28. Recent advances in drug delivery systems for targeting brain tumors10.1080/10717544.2022.2154409 ↗
29. Flow-based assembly of nucleic acid-loaded polymer nanoparticles10.1071/CH23116 ↗
30. Generation of a hydrophobic protrusion on nanoparticles to improve the membrane-anchoring ability and cellular internalization10.1002/anie.202312755 ↗
31. W. Wang, P. Wang, L. Chen, M. Zhao, C.-T. Hung, C. Yu, A. A.-Khalaf, W. N. Hozzein, F. Zhang, X. Li, D. Zhao, Engine-Trailer-Structured Nanotrucks for Efficient Nano-Bio Interactions and Bioimaging-Guided Drug Delivery, Chem 6 (2020) 1097-1112.https://doi.org/10.1016/j.chempr.2020.01.010.10.1016/j.chempr.2020.01.010 ↗
32. Rod-like mesoporous silica nanoparticles with rough surfaces for enhanced cellular delivery10.1039/C3TB21431A ↗
33. Sandwiching of MOF nanoparticles between graphene oxide nanosheets among ice grains10.1038/s41467-025-56949-w ↗
34. Overlooked spherical nanoparticles exist in plant extracts: from mechanism to therapeutic applications10.1021/acsami.2c19065 ↗
35. Gap-enhanced catalysis in gold nanostructures by electric field and curvature effects10.1021/acs.nanolett.4c06399 ↗
36. Bioinspired nanotopographical design of drug delivery systems10.1038/s44222-022-00010-8 ↗
37. Facile synthesis of uniform virus-like mesoporous silica nanoparticles for enhanced cellular internalization10.1021/acscentsci.7b00257 ↗
38. Biodegradable cascade nanocatalysts enable tumor-microenvironment remodeling for controllable CO release and targeted/synergistic cancer nanotherapy10.1016/j.biomaterials.2021.121001 ↗
39. DLS and zeta potential – what they are and what they are not?10.1016/j.jconrel.2016.06.017 ↗
40. Advanced nanostructured biomaterials for accelerated wound healing: insights into biological interactions and therapeutic innovations: a comprehensive review10.1016/j.matdes.2025.114698 ↗
41. Y. Xu, T. Fourniols, Y. Labrak, V. Préat, A. Beloqui, A. Des Rieux, Surface Modification of Lipid-Based Nanoparticles, ACS Nano 16 (2022) 7168–7196. https://doi.org/10.1021/acsnano.2c02347.10.1021/acsnano.2c02347 ↗
42. Core–shell codelivery nanocarrier synergistically regulates cartilaginous immune microenvironment for total meniscus replacement10.1021/acsnano.4c16158 ↗
43. Polyvinylpyrrolidone (PVP) in nanoparticle synthesis10.1039/C5DT02964C ↗
44. Recent advances in bone-targeted therapy10.1016/j.pharmthera.2020.107473 ↗
45. Stimulus‐responsive hydrogels as drug delivery systems for inflammation targeted therapy
46. MicroRNA-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment10.1038/s41413-023-00299-0 ↗
47. Injectable regenerated silk fibroin micro/nanosphere with enhanced permeability and stability for osteoarthritis therapy
48. Defective RuO2 nanospheres attenuate osteoarthritis progression via suppressing the ROS/NLRP3/caspase-1 signaling pathway10.1021/acsnano.5c04011 ↗
49. Balancing the anti‐bacterial and pro‐osteogenic properties of Ti‐Based Implants by partial conversion of ZnO nanorods into hybrid Zinc phosphate nanostructures
50. Hydrolysis of 2D nanosheets reverses rheumatoid arthritis through anti‐inflammation and osteogenesis10.1002/adma.202415543 ↗
51. Bioactive core–shell CaF2 upconversion nanostructure for promotion and visualization of engineered bone reconstruction10.1021/acsnano.0c08013 ↗
52. An injectable multi-functional composite bioactive hydrogel for bone regeneration via immunoregulatory and osteogenesis effects10.1007/s42114-025-01213-4 ↗
53. Pollen-like mesoporous silica nanoparticles facilitate macrophage-mediated anti-inflammatory response via physical contact cues in the osteoimmune microenvironment10.1016/j.actbio.2025.03.014 ↗
54. Triple-effect strategy with taxifolin-whitlockite nanoparticles embedded hydrogel for osteoporotic bone defect repair and bone homeostasis modulation10.1016/j.cej.2025.163133 ↗
55. ROS‐activated nanohydrogel scaffolds with multi‐factors controlled release for targeted dual‐lineage repair of osteochondral defects10.4028/b-XDTcg5 ↗
56. Charge‐guided cartilage‐penetrating micro/nanocarriers that inhibit Piezo1 and Protect cartilage to alleviate osteoarthritis
57. Sulfated chitosan-modified CuS nanocluster: a versatile nanoformulation for simultaneous antibacterial and bone regenerative therapy in periodontitis10.1021/acsnano.4c00137 ↗
58. Controlled release of ceria and ferric oxide nanoparticles via collagen hydrogel for enhanced osteoarthritis therapy
59. Bacteria‐mediated tumor‐targeting delivery of multienzyme‐mimicking covalent organic frameworks promoting pyroptosis for combinatorial sono‐catalytic immunotherapy10.1002/advs.202407133 ↗
60. Enhanced osteosarcoma immunotherapy via CaCO3 nanoparticles: remodeling tumor acidic and immune microenvironment for photodynamic therapy10.1002/adhm.202470147 ↗
61. Photothermal sensitive nanocomposite hydrogel for infectious bone defects10.1038/s41413-024-00377-x ↗
62. Controlled production of liposomes with novel microfluidic membrane emulsification for application of entrapping hydrophilic and lipophilic drugs10.1016/j.jiec.2023.10.051 ↗
63. Encapsulation, protection, and delivery of bioactive proteins and peptides using nanoparticle and microparticle systems: a review10.1016/j.cis.2018.02.002 ↗
64. Silica nanoparticles: a review of their safety and current strategies to overcome biological barriers10.1016/j.addr.2023.115115 ↗
65. J.C. Kraft, J.P. Freeling, Ziyao. Wang, R.J.Y. Ho, Emerging Research and Clinical Development Trends of Liposome and Lipid Nanoparticle Drug Delivery Systems, J. Pharm. Sci. 103 (2014) 29–52. https://doi.org/10.1002/jps.23773.10.1002/jps.23773 ↗
66. A library of polyphenol‐amino acid condensates for high‐throughput continuous flow production of nanomedicines with ultra‐high drug loading10.1002/adma.202417534 ↗
67. Advances in doxorubicin-based nano-drug delivery system in triple negative breast cancer10.3389/fbioe.2023.1271420 ↗
68. An endoplasmic reticulum stress‐specific nanoinducer selectively evokes Type‐II immunogenic cell death for pyroptotic cancer immunotherapy
69. A metal-coordination stabilized small-molecule nanomedicine with high drug-loading capacity and synergistic photochemotherapy for cancer treatment10.1039/D4NR02101K ↗
70. Synergistic chemoimmunotherapy augmentation via sequential nanocomposite hydrogel‐mediated reprogramming of cancer‐associated fibroblasts in osteosarcoma
71. Rejuvenating hyaline cartilage with senescence‐targeting Si‐ADAM19 delivery for osteoarthritis therapy10.4028/b-XDTcg5 ↗
72. K. Ma, T. Pham, J. Wang, I. O-Sullivan, A. DiCamillo, S. Du, F. Mwale, Z. Farooqui, G. Votta-Velis, B. Bruce, A.J. Van Wijnen, Y. Liu, H.-J. Im, Nanoparticle-based inhibition of vascular endothelial growth factor receptors alleviates osteoarthritis pain and cartilage damage, Sci. Adv. 10 (2024) eadi5501. https://doi.org/10.1126/sciadv.adi5501.10.1126/sciadv.adi5501 ↗
73. Programmed surface platform orchestrates anti-bacterial ability and time-sequential bone healing for implant-associated infection10.1016/j.biomaterials.2024.122772 ↗
74. An iron balance dual‐drive strategy (IBDS) promotes bone regeneration in smokers by regulating mitochondrial iron homeostasis10.1002/adma.202501933 ↗
75. Zinc finger-inspired peptide-metal-phenolic nanointerface enhances bone-implant integration under bacterial infection microenvironment through immune modulation and osteogenesis promotion
76. Innovative biomaterials for the treatment of bone cancer10.3390/ijms22158214 ↗
77. Bone‐targeting and multishelled oral eldecalcitol nanoparticles improve osteoporosis by reconstruction of osteogenic‐osteoclastic homeostasis10.1002/adfm.202404549 ↗
78. Nano-drug delivery system for the treatment of acute myelogenous leukemia10.3724/zdxbyxb-2022-0084 ↗
79. Enzyme hybrid virus-like hollow mesoporous CuO adhesive hydrogel spray through glucose-activated cascade reaction to efficiently promote diabetic wound healing10.1016/j.cej.2021.128901 ↗
80. Injections in the osteoarthritic knee: a review of current treatment options10.1302/2058-5241.6.210026 ↗
81. Bone/cartilage targeted hydrogel: strategies and applications
82. Hydrogel electrospun and composite materials for bone/cartilage and neural tissue engineering10.3390/ma14226899 ↗
83. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect10.1016/j.addr.2010.04.009 ↗
84. Active targeting schemes for nano-drug delivery systems in osteosarcoma therapeutics10.1186/s12951-023-01826-1 ↗
85. Bone-targeting nucleic acid delivery polymer vector for effective therapy of bone metastasis10.1021/acsnano.5c04743 ↗
86. An injectable multifunctional nanocomposite hydrogel promotes vascularized bone regeneration by regulating macrophages10.1186/s12951-025-03358-2 ↗
87. Smart osteoclasts targeted nanomedicine based on amorphous CaCO3 for effective osteoporosis reversal10.1186/s12951-024-02412-9 ↗
88. Controlled release mechanism of thymol loaded into mesoporous silica nanoparticles for active packaging films10.1016/j.fbio.2023.103229 ↗
89. Coaxial microfluidic spinning design produced high strength alginate membranes for antibacterial activity and drug release10.1016/j.ijbiomac.2023.124956 ↗
90. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier10.3390/polym3031377 ↗
91. J. Alipal, N.A.S. Mohd Pu’ad, T.C. Lee, N.H.M. Nayan, N. Sahari, H. Basri, M.I. Idris, H.Z. Abdullah, A review of gelatin: Properties, sources, process, applications, and commercialisation, Mater. Today Proc. 42 (2021) 240–250. https://doi.org/10.1016/j.matpr.2020.12.922.10.1016/j.matpr.2020.12.922 ↗
92. Wang · ACS Nano · 2023 · 17 · 47210.1021/acsnano.2c08982 ↗
93. Self-healing hyaluronic acid nanocomposite hydrogels with platelet-rich plasma impregnated for skin regeneration10.1021/acsnano.2c05069 ↗
94. Preparation and application of pH-responsive drug delivery systems10.1016/j.jconrel.2022.05.056 ↗
95. Recent advances of redox-responsive nanoplatforms for tumor theranostics10.1016/j.jconrel.2021.02.030 ↗
96. ROS-responsive and scavenging bifunctional hydrogel enables co-delivery of anti-inflammatory agent and osteogenetic nanoparticle for periodontitis treatment10.1016/j.matdes.2024.112777 ↗
97. Advances in the therapeutic delivery and applications of functionalized Pluronics: a critical review10.1016/j.cis.2021.102563 ↗
98. Tumor microenvironment-responsive modular integrated nanocomposites for magnetically targeted and photothermal enhanced catalytic therapy10.1007/s12274-023-5706-y ↗
99. 3D printed biomimetic composite scaffolds with sequential releasing of copper ions and dexamethasone for cascade regulation of angiogenesis and osteogenesis10.1016/j.cej.2024.153662 ↗
100. Self‐reinforced MOF‐based nanogel alleviates osteoarthritis by long‐acting drug release10.1002/adma.202470310 ↗