Metal-organic frameworks (MOFs) have become well-adaptable and versatile porous materials with a variety of potential applications in drug delivery, catalysis, sensing, and environmental remediation. However, utilization in biological systems and the environment is limited due to concerns about their chemical stability and potential toxicological behavior. The review assesses the specific factors that determine MOF toxicity while combining quantitative data from in vitro, in vivo ad environmental studies. In particular, evidence suggests Cu- and Co-based MOFs create excessive ROS via Fenton-type pathways while Zn- based MOFs, such as ZIF-8, demonstrated dose-dependent cytotoxicity due to rapid Zn2+ release under acidic conditions. Linker degradation byproducts resulted in interference with metabolism and an inflammatory response. Nanoparticles with sizes less than 100 nm displayed additional cellular uptake, mitochondrial dysfunction, and developmental issues in zebrafish embryos. Environmental exposure also revealed some degree of phytotoxicity and some shifts in microbial communities, as exemplified by biomass loss in pea seedlings exposed to MOF-199. While the available data appear to increase, the gaps in knowledge are still significant regarding long-term exposures, biodegradation considerations of the linker, bio-distribution aspects on the nanoscale, and toxicological evaluation protocols to determine standardization of MOF materials. This review summarizes existing mitigation strategies—including biocompatible metal selection, structural stabilization, and coatings with polymeric material that have decreased cytotoxity in controlled settings. As a whole, this review highlights an immediate need for mechanistic, long-term, and regulatory work to facilitate the development of safe, responsible, and sustainable use and translation of MOFs in the biomedical and industrial spheres.
ZhangQYanSYanX, et al. Recent advances in metal-organic frameworks: synthesis, application and toxicity. Sci Total Environ2023; 902: 165944.
2.
EttlingerRLächeltUGrefR, et al. Toxicity of metal-organic framework nanoparticles: from essential analyses to potential applications. Chem Soc Rev2022; 51(2). 464–484. https://doi.org/10.1039/d1cs00918d
3.
VijayasriKKumarSVermaA, et al. Toxicity of metal-organic frameworks (MOFs) in living systems. In: JainBVermaDKSinghAK (eds) Metal organic frameworks.Elsevier, 2024, pp. 263–286.
4.
TripathyDB. Recent advances on 2D metal organic framework (MOF) membrane for waste water treatment and desalination. Desalination2024; 592: 118183.
5.
KumarPAnandBTsangYF, et al. Regeneration, degradation, and toxicity effect of MOFs: opportunities and challenges. Environ Res2019; 176: 108488. https://doi.org/10.1016/j.envres.2019.05.019
6.
Tamames-TabarCCunhaDImbuluzquetaE, et al. Cytotoxicity of nanoscaled metal–organic frameworks. J Mater Chem B2014; 2(3): 262–271.
7.
AzizKHHMustafaFSHamarawfRF, et al. Adsorptive removal of toxic heavy metals from aquatic environments using metal–organic frameworks: a review. J Environ Chem Eng2025; 13: 110953.
8.
BaatiTNjimLNeffatiF, et al. In depth analysis of the in vivo toxicity of nanoparticles of porous iron(III) metal–organic frameworks. Chem Sci2013; 4(4). 1597–1607. https://doi.org/10.1039/c3sc22116d
9.
LiMYinSLinM, et al. Current status and prospects of metal-organic frameworks for bone therapy and bone repair. J Mater Chem B2022; 10(27): 5105–5128.
10.
LiuJGoetjenTAWangQ, et al. MOF-enabled confinement and related effects for chemical catalyst presentation and utilization. Chem Soc Rev2022; 51(3): 1045–1097.
11.
AbbasMLiangZChenM, et al. Toxicity challenges and current advancement in metal-organic frameworks (MOFs) for biomedical applications. Biol Trace Elem Res2026; 204: 836–852.
12.
GatouMAVagenaIALagopatiN, et al. Functional MOF-based materials for environmental and biomedical applications: a critical review. Nanomater2023; 13(15): 2224.
13.
GuanXLiQMaimaitiT, et al. Toxicity and photosynthetic inhibition of metal-organic framework MOF-199 to pea seedlings. J Hazard Mater2021; 409: 124521.
14.
SajidM. Toxicity of nanoscale metal organic frameworks: a perspective. Environ Sci Pollut Res2016; 23(15): 14805–14807.
15.
AzizKRazaNKanwalN, et al. Recent advances in nanomaterial-based adsorbents for removal of pharmaceutical pollutants from wastewater. Mater Horiz2025; 12: 6043–6068.
16.
SzaboRBodoleaCMocanT. Iron, copper, and zinc homeostasis: physiology, physiopathology, and nanomediated applications. Nanomater2021; 11(11): 2958.
17.
ChenGLengXLuoJ, et al. In vitro toxicity study of a porous iron(III) metal–organic framework. Molecules2019; 24(7): 1211.
18.
WuYSunBTangY, et al. Bone targeted nano-drug and nano-delivery. Bone Res2024; 12(1): 51.
19.
WagnerALiuQRoseOL, et al. Toxicity screening of two prevalent metal organic frameworks for therapeutic use in human lung epithelial cells. Int J Nanomedicine2019; 14: 7585–7596. https://doi.org/10.2147/IJN.S216888
20.
EmamHEDarweshOMAbdelhameedRM. In-growth metal organic framework/synthetic hybrids as antimicrobial fabrics and its toxicity. Colloids Surf B Biointerfaces2018; 165: 219–228.
21.
AzizKHHMustafaFSHamaS. Pharmaceutical removal from aquatic environments using multifunctional metal-organic frameworks (MOFs) materials for adsorption and degradation processes: a review. Coord Chem Rev2025; 542: 216875.
22.
YaghiOMO’KeeffeMOckwigNW, et al. Reticular synthesis and the design of new materials. Nature2003; 423(6941). 705–714. https://doi.org/10.1038/nature01650
23.
FurukawaHCordovaKEO’KeeffeM, et al. The chemistry and applications of metal-organic frameworks. Science2013; 341(6149). 1230444. https://doi.org/10.1126/science.1230444
24.
HussainMZYangZHuangZ, et al. Recent advances in metal-organic frameworks derived nanocomposites for photocatalytic applications in energy and environment. Adv Sci2021; 8(14): 2100625.
25.
LuWWeiZGuZ-Y, et al. Tuning the structure and function of metal-organic frameworks via linker design. Chem Soc Rev2014; 43(16). 5561–5593. https://doi.org/10.1039/c4cs00003j
26.
KimDKangMHaH, et al. Multiple functional groups in metal–organic frameworks and their positional regioisomerism. Coord Chem Rev2021; 438: 213892.
27.
MoosaviSMNandyAJablonkaKM, et al. Understanding the diversity of the metal-organic framework ecosystem. Nat Commun2020; 11(1): 4068.
28.
WiśniewskaPHaponiukJSaebMR, et al. Mitigating metal-organic framework (MOF) toxicity for biomedical applications. Chem Eng J2023; 471: 144400.
29.
ZouMDongMZhaoT. Advances in metal-organic frameworks MIL-101(Cr). Int J Mol Sci2022; 23(16): 9396.
30.
KhanSGuanQLiuQ, et al. Synthesis, modifications and applications of MILs Metal-organic frameworks for environmental remediation: the cutting-edge review. Sci Total Environ2022; 810: 152279.
31.
SadiqSKhanSKhanI, et al. A critical review on metal-organic frameworks (MOFs) based nanomaterials for biomedical applications: designing, recent trends, challenges, and prospects. Heliyon2024; 10(3): e25521.
32.
SajidM. Toxicity of nanoscale metal-organic frameworks in biological systems. In: MozafariM (ed.) Metal-organic frameworks for biomedical applications. Elsevier, 2020, pp. 497–515.
33.
HorcajadaPGrefRBaatiT, et al. Metal-organic frameworks in biomedicine. Chem Rev2012; 112(2). 1232–1268. https://doi.org/10.1021/cr200256v
34.
AhmadiMAyyoubzadehSMGhorbani-BidkorbehF, et al. An investigation of affecting factors on MOF characteristics for biomedical applications: a systematic review. Heliyon2021; 7(4): e06914.
35.
WangAWaldenMEttlingerR, et al. Biomedical metal-organic framework materials: perspectives and challenges. Adv Funct Mater2024; 34(43): 2308589.
PrakashOVermaDSinghPC. Exploring enzyme-immobilized MOFs and their application potential: biosensing, biocatalysis, targeted drug delivery and cancer therapy. J Mater Chem B2024; 12: 10198–10214.
38.
LiRChenTPanX. Metal-organic-framework-based materials for antimicrobial applications. ACS Nano2021; 15(3): 3808–3848.
39.
RuyraÀYazdiAEspínJ, et al. Synthesis, culture medium stability, and in vitro and in vivo zebrafish embryo toxicity of metal-organic framework nanoparticles. Chem Eur J2015; 21(6). 2508–2518. https://doi.org/10.1002/chem.201405380
40.
WangHPeiXKalmutzkiMJ, et al. Large cages of zeolitic imidazolate frameworks. Acc Chem Res2022; 55(5): 707–721.
41.
DingMLiuWGrefR. Nanoscale MOFs: from synthesis to drug delivery and theranostics applications. Adv Drug Deliv Rev2022; 190: 114496.
42.
TripathyDBPradhanSGuptaA, et al. Nanoparticles induced neurotoxicity. Nanotoxicology2025; 19: 325–352.
43.
TripathyDBPradhanS. Nanoparticles induced health hazards through environmental exposure and direct contact. Proceedings of the Institution of Mechanical Engineers, Part N: Journal of Nanomaterials, Nanoengineering and Nanosystems, 2025; 23977914241312438.
44.
ChenPHeMChenB, et al. Size- and dose-dependent cytotoxicity of ZIF-8 based on single cell analysis. Ecotoxicol Environ Saf2020; 205: 111110.
45.
ChattopadhyayKMandalMMaitiDK. A review on zirconium-based metal–organic frameworks: synthetic approaches and biomedical applications. Mater Adv2024; 5(1): 51–67.
46.
LiX. “Cage” nano and micro-particles for biomedical applications. Doctoral dissertation, Université Paris-Saclay, 2017.
47.
LiYWangWX. Toxic effects and action mechanism of metal-organic framework uio-66-NH2 in Microcystis aeruginosa. Environ Pollut2024; 346: 123595.
48.
MarinhoTCGomez-AvilesAHerrastiP. Metal–organic frameworks (MOFs) for adsorption and degradation of microplastics. Microplastics2025; 4(1): 11.
49.
Mohammed AmeenSSQasimFOAlhasanHS, et al. Intrinsic dual-state emission zinc-based MOF rodlike nanostructures with applications in smartphone readout visual-based detection for tetracycline: MOF-based color tonality. ACS Appl Mater Interfaces2023; 15(39): 46098–46107.
50.
Escobar-HernandezHUQuanYPapadakiMI, et al. Life cycle assessment of metal–organic frameworks: sustainability study of zeolitic imidazolate framework-67. ACS Sustain Chem Eng2023; 11(10): 4219–4225.
51.
DengLEGuoMDengY, et al. MOF-based platform for kidney diseases: advances, challenges, and prospects. Pharmaceutics2024; 16(6): 793.
52.
ChandraDKKumarAMahapatraC. Smart nano-hybrid metal-organic frameworks: revolutionizing advancements, applications, and challenges in biomedical therapeutics and diagnostics. Hybrid Adv2025; 9: 100406.
53.
BarjastehMVossoughiMBagherzadehM, et al. Green synthesis of PEG-coated MIL-100(Fe) for controlled release of dacarbazine and its anticancer potential against human melanoma cells. Int J Pharm2022; 618: 121647.
54.
HuHSuMBaH, et al. ZIF-8 nanoparticles induce neurobehavioral disorders through the regulation of ROS-mediated oxidative stress in zebrafish embryos. Chemosphere2022; 305: 13545.
55.
NabipourHRohaniS. Metal-organic frameworks for overcoming the blood-brain barrier in the treatment of brain diseases: a review. Nanomater2024; 14(17): 1379.
56.
HoferSHofstätterNPunzB, et al. Immunotoxicity of nanomaterials in health and disease: current challenges and emerging approaches for identifying immune modifiers in susceptible populations. Wiley Interdiscip Rev Nanomed Nanobiotechnol2022; 14(6): e1804.
57.
BellisarioVGarzaroGSquillaciotiG, et al. Occupational exposure to metal-based nanomaterials: a possible relationship between chemical composition and oxidative stress biomarkers. Antioxidants2024; 13(6): 676.
58.
OECD. Guidance document on aquatic and sediment toxicological testing of nanomaterials.OECD Publishing, 2020.
59.
YangLChenHKaziemAE, et al. Effects of exposure to different types of metal-organic framework nanoparticles on the gut microbiota and liver metabolism of adult zebrafish. ACS Nano2024; 18(37): 25425–25445.
60.
AttaMRAl-MahmodiAFAl-DhawiBNS, et al. MOF-based catalysts for CO2 reduction via photo-, electro-, and photoelectrocatalysis: a review. Academia Green Energy2025; 2(1): 1–23.
61.
LanSZhangJLiX, et al. Low toxicity of metal-organic framework MOF-74(Co) nano-particles in vitro and in vivo. Nanomater2022; 12(19): 3398.
62.
BeiranvandMDehghanG. An analytical review of the therapeutic application of recent trends in MIL-based delivery systems in cancer therapy. Microchimica Acta2025; 192(2): 89.
63.
GuoA. Metal-organic frameworks as bacteria mimicking delivery systems for tuberculosis.South Dakota State University, 2021.
64.
HuHSuMBaH, et al. ZIF-8 nanoparticles induce neurobehavioral disorders through the regulation of ROS-mediated oxidative stress in zebrafish embryos. Chemosphere2022; 305: 135453.
65.
PathakJ. Controlled release of carbendazim in Cu-based MoF against rice blast management under a controlled environment. Doctoral dissertation, Asian Institute of Technology, 2024.
66.
RoseOLArnoldMDinuC-Z. Electric Cell-Substrate Sensing for Real-Time Evaluation of Metal-Organic Framework Toxicological Profiles. JoVE2023; 195: e65313.
67.
CarrascoS. Metal-organic frameworks for the development of biosensors: a current overview. Biosensors2018; 8(4): 92.
68.
WiśniewskaPHaponiukJSaebMR, et al. Mitigating metal-organic framework (MOF) toxicity for biomedical applications. Chem Eng J2023; 471: 144400.
69.
YusufVFMalekNIKailasaSK. Review on metal-organic framework classification, synthetic approaches, and influencing factors: applications in energy, drug delivery, and wastewater treatment. ACS Omega2022; 7(49): 44507–44531.
70.
WambaHNSinghNDalakotiS, et al. Al-based isoreticular metal-organic frameworks with MIL-53 topology as effective adsorbents in methane purification. ChemistrySelect2023; 8(4): e202204476.
71.
XieYFangWZhangJ. Aggregation of titanium-oxo clusters. Aggreg2024; 5(3): e506.
72.
ShahzadiSAkhtarMArshadM, et al. A review on synthesis of MOF-derived carbon composites: innovations in electrochemical, environmental and electrocatalytic technologies. RSC Adv2024; 14(38): 27575–27607.
73.
DengZJLiangMMonteiroM, et al. Nanoparticle-induced unfolding of fibrinogen promotes mac-1 receptor activation and inflammation. Nat Nanotechnol2011; 6(1): 39–44.
