Metal-organic frameworks (MOFs), comprised of organic ligands and metal ions/metal clusters via coordinative bonds are highly porous, crystalline materials. Their tunable porosity, chemical composition, size and shape, and easy surface functionalization make this large family more and more popular for drug delivery. There is a growing interest over the last decades in the design of engineered MOFs with controlled sizes for a variety of biomedical applications. This article presents an overall review and perspectives of MOFs-based drug delivery systems (DDSs), starting with the MOFs classification adapted for DDSs based on the types of constituting metals and ligands. Then, the synthesis and characterization of MOFs for DDSs are developed, followed by the drug loading strategies, applications, biopharmaceutics and quality control. Importantly, a variety of representative applications of MOFs are detailed from a point of view of applications in pharmaceutics, diseases therapy and advanced DDSs. In particular, the biopharmaceutics and quality control of MOFs-based DDSs are summarized with critical issues to be addressed. Finally, challenges in MOFs development for DDSs are discussed, such as biostability, biosafety, biopharmaceutics and nomenclature.

In recent years, Metal-Organic Frameworks (MOFs) have attracted a growing interest for biomedical applications. The design of MOFs should take into consideration the subtle balance between stability and biodegradability. However, only few studies have focused on the MOFs’ stability in physiological media and their degradation mechanism. Here, we investigate the degradation of mesoporous iron (III) carboxylate MOFs, which are among the most employed MOFs for drug delivery, by a set of complementary methods. In situ AFM allowed monitoring with nanoscale resolution the morphological, dimensional, and mechanical properties of a series of MOFs in phosphate buffer saline and in real time. Depending on the synthetic route, the external surface presented either well-defined crystalline planes or initial defects, which influenced the degradation mechanism of the particles. Moreover, MOF stability was investigated under different pH conditions, from acidic to neutral. Interestingly, despite pronounced erosion, especially at neutral pH, the dimensions of the crystals were unchanged. It was revealed that the external surfaces of MOF crystals rapidly respond to in situ changes of the composition of the media they are in contact with. These observations are of a crucial importance for the design of nanosized MOFs for drug delivery applications.

Nanosized metal-organic frameworks (nanoMOFs) MIL-100(Fe) are highly porous and biodegradable materials that have emerged as promising drug nanocarriers. A challenging issue concerns their surface functionalization in order to evade the immune system and to provide molecular recognition ability, so that they can be used for specific targeting. A convenient method for their coating with tetraethylene glycol, polyethylene glycol, and mannose residues is reported herein. The method consists of the organic solvent-free self-assembly on the nanoMOFs of building blocks based on β-cyclodextrin facially derivatized with the referred functional moieties, and multiple phosphate groups to anchor to the nanoparticles’ surface. The coating of nanoMOFs with cyclodextrin phosphate without further functional groups led to a significant decrease of macrophage uptake, slightly improved by polyethylene glycol or mannose-containing cyclodextrin phosphate coating. More notably, nanoMOFs modified with tetraethylene glycol-containing cyclodextrin phosphate displayed the most efficient “stealth” effect. Mannose-coated nanoMOFs displayed a remarkably enhanced binding affinity towards a specific mannose receptor, such as Concanavalin A, due to the multivalent display of the monosaccharide, as well as reduced macrophage internalization. Coating with tetraethylente glycol of nanoMOFs after loading with doxorubicin is also described. Therefore, phosphorylated cyclodextrins offer a versatile platform to coat nanoMOFs in an organic solvent-free, one step manner, providing them with new biorecognition and/or “stealth” properties.

Recently developed, nanoscale metal-organic frameworks (nanoMOFs) functionalized with versatile coatings are drawing special attention in the nanomedicine field. Here we show the preparation of core–shell MIL-100(Al) nanoMOFs for the delivery of the anticancer drug doxorubicin (DOX). DOX was efficiently incorporated in the MOFs and was released in a progressive manner, depending on the initial loading. Besides, the coatings were made of biodegradable γ-cyclodextrin-citrate oligomers (CD-CO) with affinity for both DOX and the MOF cores. DOX was incorporated and released faster due to its affinity for the coating material. A set of complementary solid state nuclear magnetic resonance (ssNMR) experiments including ¹H-¹H and ¹³C-²⁷Al two-dimensional NMR, was used to gain a deep understanding on the multiple interactions involved in the MIL-100(Al) core–shell system. To do so, ¹³C-labelled shells were synthesized. This study paves the way towards a methodology to assess the nanoMOF component localization at a molecular scale and to investigate the nanoMOF physicochemical properties, which play a main role on their biological applications.