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Tuning the Endocytosis Mechanism of Zr-Based MetalāOrganic Frameworks through Linker Functionalization
A critical bottleneck for the use of metal-organic frameworks (MOFs) as drug delivery systems has been allowing them to reach their intracellular targets without being degraded in the acidic environment of the lysosomes. Cells take up particles by endocytosis through multiple biochemical pathways, and the fate of these particles depends on these routes of entry. Here, we show the effect of functional group incorporation into a series of Zr-based MOFs on their endocytosis mechanisms, allowing us to design an effi-cient drug delivery system. In particular, naphthalene-2,6-dicarboxylic acid and 4,4'-biphenyldicarboxylic acid ligands promote entry through the caveolin-pathway, allowing the particles to avoid lysosomal degradation and be delivered into the cytosol, en-hancing their therapeutic activity when loaded with drugs.C.A.O. thanks Becas Chile and the Cambridge Trust for funding. S.H. thanks the Cambridge Trust for funding. R.S.F. and D.F.-J. thank the Royal Society for the receipt of University Research Fellowships. D.F.-J. thanks financial support from ERC-2016-COG 726380. R.S.F., R.J.M., and I.A.L. thank the University of Glasgow and the EPSRC (EP/L004461/1) for funding. G.B., I.I., and D.M. acknowledge the financial support from 2014-SGR-80, MAT2015-65354-C2-1-R and EU FP7 ERC-Co 615954. ICN2 received support from the Spanish MINECO through the Severo Ochoa Centers of Excellence Program, under Grant No. SEV-2013-0295