Bioactive substances delivery for bone repair via nanocomposites: advantages, mechanisms, and emerging trends_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

MA Yanming ¹ , DU Zhipo ² ^{共同第一作者} ,  WANG Jianbo ² ,  LI Xiaoming ¹

1. Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing Advanced Innovation Center for Biomedical Engineering, Beijing, 100083, P. R. China;
2. Department of Orthopedics, the Fourth Central Hospital of Baoding City, Baoding Hebei, 072350, P. R. China;

Corresponding?author：

WANG Jianbo, Email: 15632261377@163.com; LI Xiaoming, Email: lixm@buaa.edu.cn

Keywords：

Nanocomposites; bioactive substances; controllable delivery; bone repair

DOI：

10.7507/1002-1892.202511049

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective The advantages, mechanisms, and advances in nanocomposites for delivering bioactive substances in bone tissue engineering were systematically reviewed. Methods This review provides a comprehensive analysis by conducting an in-depth retrieval of relevant literature and integrating it with related work from our research team. Results Capitalizing on their inherent size effects and tunable structures, nanocomposites exhibit high drug-loading capacity and controlled/targeted delivery, allowing for the co-delivery of diverse molecules. This smart delivery capability, responsive to specific pathological or external cues, facilitates on-demand precision release to execute multiple therapeutic functions, including osteogenesis, antibacterial action, and immunomodulation. Conclusion Nanocomposites demonstrate high delivery efficiency and controlled release kinetics, with the potential for future clinical translation of their multi-signal responsive and spatiotemporally precise drug release capabilities.

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2.	Gil CJ, Li L, Hwang B, et al. Tissue engineered drug delivery vehicles: Methods to monitor and regulate the release behavior. J Control Release, 2022, 349: 143-155.
3.	Moradi Kashkooli F, Jakhmola A, Hornsby TK, et al. Ultrasound-mediated nano drug delivery for treating cancer: Fundamental physics to future directions. J Control Release, 2023, 355: 552-578.
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28.	Zhang Y, Song Q, Yang S, et al. Revitalizing osteoporotic bone repair via multilevel ROS scavenging and osteoimmune regulating hydrogel. Composites Part B: Engineering, 2025, 297: 112305. doi: 10.1016/j.compositesb.2025.112305.
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33.	Chen F, Wang W, Zhao H, et al. MXene-based cartilage-adhesive microspheres for photothermal-controlled hydrophobic drug release and mesenchymal stem cell delivery in osteoarthritis. ACS Nano, 2025, 19(22): 20502-20515.
34.	Liu S, Han Z, Hao JN, et al. Engineering of a NIR-activable hydrogel-coated mesoporous bioactive glass scaffold with dual-mode parathyroid hormone derivative release property for angiogenesis and bone regeneration. Bioact Mater, 2023, 26: 1-13.
35.	Li BY, Lin TY, Lai YJ, et al. Engineering multiresponsive alginate/PNIPAM/carbon nanotube nanocomposite hydrogels as on-demand drug delivery platforms. Small, 2025, 21(12): e2407420. doi: 10.1002/smll.202407420.
36.	Yu X, Liu H, Chen L, et al. Thermosensitive antibacterial nanocomposite hydrogel guiding macrophage polarization and bone regeneration for periodontitis treatment. Bioact Mater, 2025, 55: 376-390.
37.	Li W, Zhong J, Wang X, et al. Intelligent responsive zeolitic imidazolate framework-8@copper oxide nanocomposite 3D-printed scaffolds for efficient repair of infected bone defects. ACS Nano, 2025, 19(39): 35154-35180.
38.	Li Y, Feng X, Li Y, et al. Icariin-loaded selenium-gold multi-shell nanocomposites with NIR-Ⅱ response release to relieve post-damaged bone microenvironment for osteoporosis synergy therapy. Chemical Engineering Journal, 2024, 499: 156421. doi: 10.1016/j.cej.2024.156421.
39.	Zhang B, Zhi J, Wei H, et al. Enzyme-responsive assembly of cysteine-terminated heparan sulfate proteoglycan ligands for osteoinductive biphasic scaffold formation. ACS Materials Letters, 2025, 7(8): 3017-3025.
40.	Peng H, Qiu X, Cheng M, et al. Resveratrol-loaded nanoplatform RSV@DTPF promote alveolar bone regeneration in OVX rat through remodeling bone-immune microenvironment. Chemical Engineering Journal, 2023, 476: 146615. doi: 10.1016/j.cej.2023.146615.
41.	Richter RF, Vater C, Korn M, et al. Treatment of critical bone defects using calcium phosphate cement and mesoporous bioactive glass providing spatiotemporal drug delivery. Bioact Mater, 2023, 28: 402-419.
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59.	Wu Y, Zhou C, Xie J, et al. Functional iron oxide nanoparticles cross-linked hydrogel for craniofacial bone regeneration. Biomaterials, 2026, 327: 123782. doi: 10.1016/j.biomaterials.2025.123782.
60.	Wang B, Xiao S, Liao J, et al. Directional biomimetic scaffold-mediated cell migration and pathological microenvironment regulation accelerate diabetic bone defect repair. ACS Nano, 2025, 19(36): 32382-32404.

1. Shang S, Li X, Wang H, et al. Targeted therapy of kidney disease with nanoparticle drug delivery materials. Bioact Mater, 2024, 37: 206-221.
2. Gil CJ, Li L, Hwang B, et al. Tissue engineered drug delivery vehicles: Methods to monitor and regulate the release behavior. J Control Release, 2022, 349: 143-155.
3. Moradi Kashkooli F, Jakhmola A, Hornsby TK, et al. Ultrasound-mediated nano drug delivery for treating cancer: Fundamental physics to future directions. J Control Release, 2023, 355: 552-578.
4. Shetty K, Bhandari A, Yadav KS. Nanoparticles incorporated in nanofibers using electrospinning: A novel nano-in-nano delivery system. J Control Release, 2022, 350: 421-434.
5. Hughes KJ, Cheng J, Iyer KA, et al. Unveiling trends: Nanoscale materials shaping emerging biomedical applications. ACS Nano, 2024, 18(26): 16325-16342.
6. Lv Z, Ji Y, Wen G, et al. Structure-optimized and microenvironment-inspired nanocomposite biomaterials in bone tissue engineering. Burns Trauma, 2024, 12: tkae036. doi: 10.1093/burnst/tkae036.
7. Rajabifar N, Alemi MH, Rostami A, et al. 3D printing of hydrogel nanocomposites: A symbiotic union for advanced biomedical applications. Adv Colloid Interface Sci, 2025, 344: 103602. doi: 10.1016/j.cis.2025.103602.
8. Guo Y, Wang Y, Guo Y, et al. NIR‐inducible pyroelectric nanocomposite membrane promotes macrophage reprogramming for superior bone regeneration. Advanced Functional Materials, 2025, 35(37): 2502329. doi: 10.1002/adfm.202502329.
9. Mao Y, Zhang Y, Wang Y, et al. A multifunctional nanocomposite hydrogel with controllable release behavior enhances bone regeneration. Regen Biomater, 2023, 10: rbad046. doi: 10.1093/rb/rbad046.
10. Yu Y, Liao P, Gong Z, et al. Organic-inorganic multiscale crosslinking assembly for ultrahigh-toughness nanocomposites. Adv Mater, 2025, 37(41): e08572. doi: 10.1002/adma.202508572.
11. Venkata Prathyusha E, Gomte SS, Ahmed H, et al. Nanostructured polymer composites for bone and tissue regeneration. Int J Biol Macromol, 2025, 284(Pt 1): 137834. doi: 10.1016/j.ijbiomac.2024.137834.
12. Gupta P, Sharma S, Jabin S, et al. Chitosan nanocomposite for tissue engineering and regenerative medicine: A review. Int J Biol Macromol, 2024, 254(Pt 1): 127660. doi: 10.1016/j.ijbiomac.2023.127660.
13. Ribeiro MEA, Huaman NRC, Folly MM, et al. A potential hybrid nanocomposite of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) and fullerene for bone tissue regeneration and sustained drug release against bone infections. Int J Biol Macromol, 2023, 251: 126531. doi: 10.1016/j.ijbiomac.2023.126531.
14. Wahajuddin None, Arora S. Superparamagnetic iron oxide nanoparticles: magnetic nanoplatforms as drug carriers. Int J Nanomedicine, 2012, 7: 3445-3471.
15. Beach MA, Nayanathara U, Gao Y, et al. Polymeric nanoparticles for drug delivery. Chem Rev, 2024, 124(9): 5505-5616.
16. Wang J, Gao N, Wei J, et al. Chiral gold nanoparticles manipulate osteoimmune microenvironment via macrophage autophagy for bone regeneration. Mater Today Bio, 2025, 34: 102131. doi: 10.1016/j.mtbio.2025.102131.
17. Chu X, Zhang L, Li Y, et al. NIR responsive doxorubicin-loaded hollow copper ferrite @ polydopamine for synergistic chemodynamic/photothermal/chemo-therapy. Small, 2023, 19(7): e2205414. doi: 10.1002/smll.202205414.
18. Jiang J, Cai C, Li S, et al. Triple-effect strategy with taxifolin-whitlockite nanoparticles embedded hydrogel for osteoporotic bone defect repair and bone homeostasis modulation. Chemical Engineering Journal, 2025, 515: 163133. doi: 10.1016/j.cej.2025.163133.
19. Wu S, Shuai Y, Qian G, et al. A spatiotemporal drug release scaffold with antibiosis and bone regeneration for osteomyelitis. J Adv Res, 2023, 54: 239-249.
20. Li X, Zhang Z, Xie J, et al. A smart injectable hydrogel with dual responsivity to arginine gingipain a and reactive oxygen species for multifunctional therapy of periodontitis. Small, 2025, 21(23): e2408034. doi: 10.1002/smll.202408034.
21. Zhang Q, Natarajan D, Gao W, et al. Neodymium-doped mesoporous silica nanoparticles promote bone regeneration via autophagy-mediated macrophage immunomodulation. Mater Today Bio, 2025, 34: 102198. doi: 10.1016/j.mtbio.2025.102198.
22. Li Y, Li W, Li L, et al. Treating critical bone defects by using core-shell biological scaffold to regulate fibrosis-osteogenic homeostasis. Mater Today Bio, 2025, 31: 101560. doi: 10.1016/j.mtbio.2025.101560.
23. He C, He P, Ou Y, et al. Rectifying the crosstalk between the skeletal and immune systems improves osteoporosis treatment by core-shell nanocapsules. ACS Nano, 2025, 19(5): 5549-5567.
24. Janmohammadi M, Nazemi Z, Salehi AOM, et al. Cellulose-based composite scaffolds for bone tissue engineering and localized drug delivery. Bioact Mater, 2022, 20: 137-163.
25. Zhao Y, Xiong Y, Zhao Y. Beyond drug delivery: metal-organic framework-derived nanosystems for bone regeneration under complicated pathological microenvironments. Accounts of Materials Research, 2024, 5(12): 1532-1543.
26. Xiao R, Zhou G, Wen Y, et al. Recent advances on stimuli-responsive biopolymer-based nanocomposites for drug delivery. Composites Part B: Engineering, 2023, 266: 111018. doi: 10.1016/j.compositesb.2023.111018.
27. Yang X, Yang X, Luo P, et al. Novel one-pot strategy for fabrication of a pH-Responsive bone-targeted drug self-frame delivery system for treatment of osteoporosis. Mater Today Bio, 2023, 20: 100688. doi: 10.1016/j.mtbio.2023.100688.
28. Zhang Y, Song Q, Yang S, et al. Revitalizing osteoporotic bone repair via multilevel ROS scavenging and osteoimmune regulating hydrogel. Composites Part B: Engineering, 2025, 297: 112305. doi: 10.1016/j.compositesb.2025.112305.
29. He W, Xu T, Wang M, et al. ROS-scavenging nanomaterials as emerging tools for bone tissue regeneration: a comprehensive review of recent progress. Acta Pharmaceutica Sinica B, 2025. doi: 10.1016/j.apsb.2025.09.040.
30. Zhang R, Stehle Y, Chen L, et al. Multifunctional, enzyme/pH-responsive gelatin microspheres with aptamer-targeted antibacterial and ionic-mediated dual therapy for infected bone defects. Biomaterials, 2026, 326: 123642. doi: 10.1016/j.biomaterials.2025.123642.
31. Wu X, Wang F, Li R, et al. Enzyme-programmable DNA-PEG hydrogel spatiotemporally regulates bone regeneration microenvironment. Adv Mater, 2025, 2: e14461. doi: 10.1002/adma.202514461.
32. Wan Z, Dong Q, Liu Y, et al. Programmed biomolecule delivery orchestrate bone tissue regeneration via MSC recruitment and epigenetic modulation. Chemical Engineering Journal, 2022, 438: 135518. doi: 10.1016/j.cej.2022.135518.
33. Chen F, Wang W, Zhao H, et al. MXene-based cartilage-adhesive microspheres for photothermal-controlled hydrophobic drug release and mesenchymal stem cell delivery in osteoarthritis. ACS Nano, 2025, 19(22): 20502-20515.
34. Liu S, Han Z, Hao JN, et al. Engineering of a NIR-activable hydrogel-coated mesoporous bioactive glass scaffold with dual-mode parathyroid hormone derivative release property for angiogenesis and bone regeneration. Bioact Mater, 2023, 26: 1-13.
35. Li BY, Lin TY, Lai YJ, et al. Engineering multiresponsive alginate/PNIPAM/carbon nanotube nanocomposite hydrogels as on-demand drug delivery platforms. Small, 2025, 21(12): e2407420. doi: 10.1002/smll.202407420.
36. Yu X, Liu H, Chen L, et al. Thermosensitive antibacterial nanocomposite hydrogel guiding macrophage polarization and bone regeneration for periodontitis treatment. Bioact Mater, 2025, 55: 376-390.
37. Li W, Zhong J, Wang X, et al. Intelligent responsive zeolitic imidazolate framework-8@copper oxide nanocomposite 3D-printed scaffolds for efficient repair of infected bone defects. ACS Nano, 2025, 19(39): 35154-35180.
38. Li Y, Feng X, Li Y, et al. Icariin-loaded selenium-gold multi-shell nanocomposites with NIR-Ⅱ response release to relieve post-damaged bone microenvironment for osteoporosis synergy therapy. Chemical Engineering Journal, 2024, 499: 156421. doi: 10.1016/j.cej.2024.156421.
39. Zhang B, Zhi J, Wei H, et al. Enzyme-responsive assembly of cysteine-terminated heparan sulfate proteoglycan ligands for osteoinductive biphasic scaffold formation. ACS Materials Letters, 2025, 7(8): 3017-3025.
40. Peng H, Qiu X, Cheng M, et al. Resveratrol-loaded nanoplatform RSV@DTPF promote alveolar bone regeneration in OVX rat through remodeling bone-immune microenvironment. Chemical Engineering Journal, 2023, 476: 146615. doi: 10.1016/j.cej.2023.146615.
41. Richter RF, Vater C, Korn M, et al. Treatment of critical bone defects using calcium phosphate cement and mesoporous bioactive glass providing spatiotemporal drug delivery. Bioact Mater, 2023, 28: 402-419.
42. Kong X, Liu H, Chen S, et al. Bioengineered bacterial extracellular vesicles for targeted delivery of an osteoclastogenesis-inhibitory peptide to alleviate osteoporosis. J Control Release, 2025, 382: 113751. doi: 10.1016/j.jconrel.2025.113751.
43. Xie C, Liang R, Ye J, et al. High-efficient engineering of osteo-callus organoids for rapid bone regeneration within one month. Biomaterials, 2022, 288: 121741. doi: 10.1016/j.biomaterials.2022.121741.
44. Nikolova MP, Chavali MS. Recent advances in biomaterials for 3D scaffolds: A review. Bioact Mater, 2019, 4: 271-292.
45. Makkar S, Rana N, Priyadarshi N, et al. Unravelling the therapeutic properties of aptamer-modified exosome nanocomposite. Adv Colloid Interface Sci, 2025, 342: 103517. doi: 10.1016/j.cis.2025.103517.
46. Guo J, Wang F, Hu Y, et al. Exosome-based bone-targeting drug delivery alleviates impaired osteoblastic bone formation and bone loss in inflammatory bowel diseases. Cell Rep Med, 2023, 4(1): 100881. doi: 10.1016/j.xcrm.2022.100881.
47. Hui T, Fu J, Zheng B, et al. Subtractive nanopore engineered mxene photonic nanomedicine with enhanced capability of photothermia and drug delivery for synergistic treatment of osteosarcoma. ACS Appl Mater Interfaces, 2023, 15(43): 50002-50014.
48. Zorrón M, Cabrera AL, Sharma R, et al. Emerging 2D nanomaterials-integrated hydrogels: Advancements in designing theragenerative materials for bone regeneration and disease therapy. Adv Sci (Weinh), 2024, 11(31): e2403204. doi: 10.1002/advs.202403204.
49. Wan S, Chen Y, Huang C, et al. Scalable ultrastrong MXene films with superior osteogenesis. Nature, 2024, 634(8036): 1103-1110.
50. Xu P, He J, Xu T, et al. Synergistic integration of extracellular vesicles and metal-organic frameworks: unlocking new opportunities in disease diagnosis and therapy. Theranostics, 2025, 15(16): 8609-8638.
51. Si Y, Liu H, Li M, et al. An efficient metal-organic framework-based drug delivery platform for synergistic antibacterial activity and osteogenesis. J Colloid Interface Sci, 2023, 640: 521-539.
52. Wei R, Hu S, Wang J, et al. Oral delivery of teriparatide utilizing biocompatible transferrin-engineered MOF nanoparticles for osteoporosis therapy. Mater Today Bio, 2025, 35: 102318. doi: 10.1016/j.mtbio.2025.102318.
53. Zhang B, Chen J, Zhu Z, et al. Advances in Immunomodulatory MOFs for Biomedical Applications. Small, 2024, 20(11): e2307299. doi: 10.1002/smll.202307299.
54. Dong J, Zhou W, Hu X, et al. Honeycomb-inspired ZIF-sealed interface enhances osseointegration via anti-infection and osteoimmunomodulation. Biomaterials, 2024, 307: 122515. doi: 10.1016/j.biomaterials.2024.122515.
55. Zhang H, Ren B, Huang Y, et al. Functionalized smart platforms of ZIF-8: progress in orthopedic therapeutic applications and challenges. Chemical Engineering Journal, 2025, 524: 169386. doi: 10.1016/j.cej.2025.169386.
56. Qin Y, Zhang Z, Guo X, et al. A bone‐targeting hydrogen sulfide delivery system for treatment of osteoporotic fracture via macrophage reprogramming and osteoblast‐osteoclast coupling. Advanced Functional Materials, 2025, 35(17): 2418822. doi: 10.1002/adfm.202418822.
57. Niu X, Xiao S, Huang R, et al. ZIF-8-modified hydrogel sequentially delivers angiogenic and osteogenic growth factors to accelerate vascularized bone regeneration. J Control Release, 2024, 374: 154-170.
58. Wang Y, Zhou X, Jiang J, et al. Carboxymethyl chitosan-enhanced multi-level microstructured composite hydrogel scaffolds for bone defect repair. Carbohydr Polym, 2025, 348(Pt B): 122847. doi: 10.1016/j.carbpol.2024.122847.
59. Wu Y, Zhou C, Xie J, et al. Functional iron oxide nanoparticles cross-linked hydrogel for craniofacial bone regeneration. Biomaterials, 2026, 327: 123782. doi: 10.1016/j.biomaterials.2025.123782.
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