Multifunctional Efficiency: Extending the Concept of Atom Economy to

Multifunctional Efficiency: Extending the Concept of Atom Economy to Functional Nanomaterials Ralph Freund,† Ulrich Lac̈ helt,‡ Tobias Gruber,§ Bastian Rühle,∥ and Stefan Wuttke*,†,⊥ †

Department of Chemistry and ‡Pharmaceutical Biotechnology, Department of Pharmacy, Center for NanoScience (CeNS), University of Munich (LMU), 81377 Munich, Germany § School of Pharmacy and ⊥School of Chemistry, Joseph Banks Laboratories, University of Lincoln, Lincoln LN6 7TS, United Kingdom ∥ Federal Institute for Materials Research and Testing (BAM), Richard-Willstaetter-Str. 11, 12489 Berlin, Germany ABSTRACT: Green chemistry, in particular, the principle of atom economy, has defined new criteria for the efficient and sustainable production of synthetic compounds. In complex nanomaterials, the number of embedded functional entities and the energy expenditure of the assembly process represent additional compound-associated parameters that can be evaluated from an economic viewpoint. In this Perspective, we extend the principle of atom economy to the study and characterization of multifunctionality in nanocarriers, which we define as “multifunctional efficiency”. This concept focuses on the design of highly active nanomaterials by maximizing integrated functional building units while minimizing inactive components. Furthermore, synthetic strategies aim to minimize the number of steps and unique reagents required to make multifunctional nanocarriers. The ultimate goal is to synthesize a nanocarrier that is highly specialized but practical and simple to make. Owing to straightforward crystal engineering, metal−organic framework (MOF) nanoparticles are an excellent example to illustrate the idea behind this concept and have the potential to emerge as next-generation drug delivery systems. Here, we highlight examples showing how the combination of the properties of MOFs (e.g., their organic−inorganic hybrid nature, high surface area, and biodegradability) and induced systematic modifications and functionalizations of the MOF’s scaffold itself lead to a nanocarrier with high multifunctional efficiency. tom economy, first proposed by Barry Trost,1,2 is defined as the percentage of atoms of the desired product in relation to the total number of atoms of involved reactants during a reaction. An ideal chemical reaction would convert all atoms from the starting material into the desired product (100% atom economy, Figure 1). Thus, the atom economy defines the efficiency of a chemical reaction and is widely used to measure the “greenness” of a synthesis. The development of this field was promoted mainly by synthetic chemists attempting to synthesize chemicals with higher atom economy.1−3 However, this concept can and should be applied to measure synthesis efficiencies in general, including the synthesis efficiency of functional materials. The term “functional materials” can be used to describe a variety of material classes,4−16 but in this Perspective, we define a functional material as a compound that exhibits properties that qualify it to be utilized for a specific nontrivial purpose or to fulfill a certain task. Ideal atom economy for a functional material would mean that all starting materials are converted into product (Figure 1). Since functional materials are often complicated, we need a more elaborate metric to characterize their synthetic efficiencies accurately.

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A functional material can possess many functionalities that work together to serve a specific purpose. Functional nanocarriers, for example (i.e., nanostructured drug delivery devices capable of bypassing extra- and intracellular biological barriers to deliver the active agent at the desired site of action),17−26 have to fulfill several requirements and accomplish diverse tasks during the delivery process (e.g., stable drug loading, favorable biodistribution, target tissue accumulation, target cell uptake, endosomal escape, controlled drug release). Hence, they must possess different functionalities (Box 1 and Figure 2). The principle of atom economy is a basic method for measuring the efficacy of nanocarrier assembly. To assess the efficiency of a functional nanoconstruct more accurately, we must also consider the portion of functional/nonfunctional components and the number of synthetic steps required to produce these multifunctional products. We term this method of assessment “multifunctional efficiency” (Box 2). We suggest evaluating the synthesis of a functional material not only based on yield and product selectivity (e.g., atom economy) but also

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DOI: 10.1021/acsnano.8b00932 ACS Nano XXXX, XXX, XXX−XXX

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we encourage fundamental rethinking of the synthesis of functional materials. Next, we highlight this principle for the synthesis of metal− organic framework (MOF) nanocarriers. Metal−organic frameworks are crystalline organic−inorganic hybrid network structures that are assembled from inorganic building units (IBUs) and organic building units (OBUs).46−48 Four characteristics of MOFs make them uniquely interesting to researchers: crystallinity, tunable porosity, strong metal−ligand interactions, and structural diversity. Their crystallinity, chemically functionalizable pores, and potential systematic structural variation are some of the factors that enable researchers to design precise materials for a particular application such as fuel storage, gas capture and separation, energy, or catalysis.49−51 Metal−organic framework nanoparticles (MOF NPs) combine the crystal engineering of MOF bulk chemistry with the surface- and size-dependent properties of the nanoworld and could provide novel platforms for functional nanodevices.52−55 Different research groups have reported pioneering examples of MOF NPs as transport vehicles for the delivery of different biologically active molecules (see refs 56−66 for representative articles and refs 52 and 67−74 for reviews). In these cases, researchers exploited the extremely large available surface area of MOF NPs to load large amounts of cargo into the frameworks’ pores. Nevertheless, current research in MOFbased nanocarriers exploits the possibility of pore engineering offered by the MOF chemistry to synthesize highly functional nanocarriers in a more efficient way. The porous backbone of the MOF NP itself, consisting of IBUs and OBUs, can be used to add functionality to the carrier. In this Perspective, we highlight these important research efforts as they are useful examples for improving the multifunctional efficiency of a nanocarrier. Metal Doping of Metal−Organic Framework Scaffolds Generating Versatile Nanoagents for Microwave-Assisted Cancer Treatment. The report on cancer treatment by Fu et al. in this issue of ACS Nano is a good example of using the properties inherent in MOF structures for a specific application and making use of selective functionalization in the MOF’s scaffold for greatly improved NP performance.75 High porosity and, therefore, record-setting high specific surface areas, paired with in vivo degradability were combined in a microwave-active MOF nanoagent. The ultrahigh porosity improves confined inelastic collision of ions (Figure 3a1), leading to high microwave heating efficiencies (28.7%), thus enabling the MOF to act as an agent for microwave thermal therapy (MTT) in tumors. However, due to ablation area limitations, MTT alone often shows high tumor recurrence rates after treatment. Taking advantage of the possibility to functionalize the MOF scaffold, therapeutic functionality can be implemented in addition to “standard” MTT by metalation of the MOF itself: partial replacement of the IBU’s zirconium metal cations with manganese cations can be used to endow the MOF nanoagent with peroxidase-like catalytic activity for the production of hydroxyl radicals, a reactive oxygen species (ROS), through decomposition of hydrogen peroxide under microwave irradiation (Figure 3a2). Because hydroxyl radicals show high cytotoxicity but can also be cleared out by the antioxidation system, this functionalization enables researchers to use the Mn-doped NPs as nanoagents without adverse side effects in microwave dynamic therapy (MDT). The resulting synergistic effects of MTT and MDT cause a significant

Figure 1. Visualization of the principle of atom economy: the total conversion of the starting materials into the product without any waste (100% atom economy). Further, this example illustrates the idea of multifunctional efficiency (MFE): five building units (BUs) each with one function, i.e., five functional units (FUs), are being assembled into one nanoparticle in a one-pot synthesis, i.e., one process step (PRS) (5 BUs, 5 FUs, 1 PRS gives a MFE of 5, Box 1).

with regard to the specific tasks the material can fulfill (number of functional units, FUs) and the simplicity of the production process (number of process steps, PRSs; Box 2). Box 2 defines different parameters needed for the characterization and assessment of a nanocarrier and its production process. The functionality ratio (FR) is the fraction of FUs in relation to the total number of components and measures a kind of molecular economy with respect to functionality. The process efficiency (PE) represents the number of FUs on average that are integrated into the nanocarrier per PRS. Finally, the multifunctional efficiency (MFE) involves both parameters FR and PE and results in a measure that values both a high degree of functionality and a facile manufacturing process. A MFE of 1 expresses a high degree of multifunctional efficiency; values of MFE < 1 are suboptimal, and a MFE > 1 represents extraordinary high efficiency. The following examples are intended to illustrate the concept: 1. A nanocarrier that is produced from one building unit (BU) in the first step, loaded with a drug in the second step, and sealed with a controlled release coating in a third step has a MFE of 1 (3 BUs, 3 FUs, 3 PRSs). 2. A nanocarrier that is produced by synthesizing a monolithic nanoparticle scaffold without specific function in a first step, modified with a polymer for drug loading capability in a second step, and finally loaded with the drug in a third step has a MFE of 0.7 (3 BUs, 2 FUs, 3 PRSs). 3. A nanocarrier that only consists of five functional units that self-assemble in one single step has a MFE of 5 (5 BUs, 5 FUs, 1 PRS, Figure 1). Despite efforts to produce highly functionalized nanocarriers, most of the few nanomedicine formulations that have received market approval thus far are based on comparatively simple compositions. Researchers tend to focus on creating increasingly complex nanosystems and lose sight of the potential for clinical translation. As a general rule, the simpler the synthesis and the higher the MFE of a drug-based nanocarrier, the higher are its chances of reaching relevant clinical applications. Therefore, in defining the term “multifunctional efficiency”, B


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MOF NPs with the properties that result from systematic modification and functionalization in the MOF scaffold can lead to highly functionalized NPs (for the MFE see Box 3) that feature improved therapeutic performance. Metal−Organic Frameworks as Contrast Agents in Magnetic Resonance Imaging. Although the treatment of diseases is an important concern, imaging techniques to reveal pathogenic abnormalities like tumors in the human body at an early stage are just as crucial. Contrast agents are an important tool for improved contrast in clinical examination methods like magnetic resonance imaging (MRI) and are commonly based on metal chelates, which show high physiological stability and, thus, enable the use of toxic metals, such as gadolinium, without biocompatibility issues. However, to avoid bioaccumulation and even minimal risks of side effects, modern research is working on substituting toxic metals with nontoxic ones, such as iron.

In defining the term “multifunctional efficiency”, we encourage fundamental rethinking of the synthesis of functional materials. inhibition of tumor growth, which is greater than that resulting from MDT or MTT alone. Colloidal stability and biocompatibility of the MOF NPs were ensured by external surface modifications using aminoterminated poly(ethylene glycol). The catalytic production of cytotoxins as well as hyperthermia under microwave irradiation enable the NPs to be biosafe, therapeutic nanoagents for noninvasive cancer treatment in vivo. Moreover, the NPs can readily be obtained in a one-pot hydrothermal synthesis. This example illustrates how combining the properties inherent in C


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Figure 2. Graphical illustration of the key aspects for a clinical nanocarrier. (1) Applicability: a simple, scalable, and profitable synthesis. (2) Controlled biodistribution: (a) travel within the body to a biological target area and, specifically, to the target by (b) passive targeting, e.g., using the enhanced permeability and retention effect, or by (c) active targeting, using targeting ligands binding to receptors of the target cell. (3) Endosomal escape: a specific function of the nanocarrier enables the escape of intracellular vesicles after internalization. (4) Controlled drug release: the endosomal escape in combination with a triggered drug release function enables the drug to reach its target within the cell to unfold its effect. (5) Tailorable design: enables the nanocarrier to adapt flexibly to different needs. (6) Toxicity: decomposition of the nanocarrier into the biocompatible building block units guarantees low toxicity and fast elimination from the body after the drug’s delivery.

additional postsynthetic functionalization. The functionalized MOF NPs showed unchanged crystallinity, good cellular uptake without cytotoxity, and sufficient MR activity to enable visualization by means of clinical MRI. Therefore, these multifunctional contrast agents could be used in applications such as in vivo investigations of MOF biodistribution (e.g., accumulation in tumors) paired with the above-described advantages of MOF NPs. Creation of Radioactive Metal−Organic Frameworks for Positron Emission Imaging. A different clinical imaging technique, positron emission tomography (PET), can also be combined with the unique features of MOFs. In a previous issue of ACS Nano, Chen et al. developed radioactive NPs for PET imaging based on the radioactive PE isotope zirconium-89

Furthermore, the transition from classic contrast agents to MOF-based ones (i.e., embedding the MR-active material into the MOF scaffold) is highly desirable as it combines improved imaging and the advantageous properties of MOF NPssuch as loading them with high drug payloads for controlled, targeted drug deliverywith possible surface engineering.68 However, as opposed to metal chelates, MOF NPs show much lower physiological stability, and consequently, moving to nontoxic metals is unavoidable.45,76 Based on this premise, Zimpl et al. studied the MR activity of surface-functionalized iron-based MOF NPs as contrast agents for MRI (Figure 3b).77 Different surface modifications were employed to mediate surface shielding and to increase colloidal and physiological stability, as well as to enable subsequent fluorescent labeling or D


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into the physiologically stable MOF scaffold (Figure 3c). Further improvements in stability and dispersity, as well as additional functionalization sites for the integration of tumortargeting molecules, were achieved by surface functionalization. All these properties are a result of functionalization; however, the MOF’s inherent features are being used, as well: the highly porous framework can be loaded with doxorubicin (DOX) (Figure 3c), an anticancer drug and fluorophore, with a loading capacity of up to 1 mg of DOX per mg of MOF for enhanced drug delivery. The resulting MOF NPs show good tumor uptake and provide good tumor contrast, without evidence of toxicity or side effects (for the MFE, see Box 3). However, the release mechanism of anticancer drugs needs further improvement through additional functionalization and a better understanding of the host−guest interactions between the porous framework and the drug payload. Programming the Guest Molecule Loading and Release Profile of Metal−Organic Frameworks. The outstanding features of MOF materials are their record-setting high surface areas and chemical modifiability, leading to many different potential applications. However, many of these applications, especially the delivery of active agents, depend strongly on the host−guest interactions taking place within the pores. Therefore, understanding and control over the kinetics of these interactions is of utmost importance. During delivery

The report on cancer treatment by Fu et al. in this issue of ACS Nano is a good example of using the properties inherent in the metal−organic framework (MOF) structure for a specific application and making use of selective functionalization in the MOF’s scaffold for greatly improved NP performance. (89Zr, t1/2 = 78.4 h), whose long half-life enables elongated examination times post-injection.78 Positrons can be generated by proton-rich atoms, which achieve stability by converting a proton to a neutron and a positron. The positron, an antielectron that is equal in mass to an electron but carries a positive charge, gives rise to two photons emitted in almost exactly opposed directions when interacting with matter through a process known as electron−positron annihilation. A ring-shaped detector surrounding the patient enables the machine to detect these emitted photons and to reconstruct an image.79 The 89Zr-based MOF can be synthesized simply by partially replacing the nonradioactive isotopes with the radioactive 89Zr during synthesis, incorporating it seamlessly E


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Figure 3. Overview of the different concepts used to functionalize metal−organic framework nanoparticles (MOF NPs) scaffold for a variety of applications. (a) Microwave-assisted cancer treatment: (1) improved inelastic collisions of ions facilitated by pore confinement improve microwave thermal therapy; (2) Mn doping results in peroxidase-like activity for the catalysis of hydroxyl radical formation. (b) Taking advantage of the magnetic resonance (MR) activity of certain metal ions enables the use of MOFs as contrast agents in MR imaging. (c) Incorporation of certain radioactive metal ions into the MOF scaffold for positron emission tomography imaging. Further loading of the MOF with active agents is possible. (d) Tuning host−guest interactions by the incorporation of different functionalizations into the pore environment. (e) Integration of active agents into the MOF scaffold. Further loading of the MOF with active agents enables the delivery of multiple therapeutic components. (f) Guaranteeing high biocompatibility of the MOF by the assembly of biocompatible building units: here, a MOF built from a protein as an inorganic building unit. (g) The ship in the bottle: encapsulation of active agents into the MOF that are too big to pass the pore aperture. (h) Using MOFs for photodynamic therapy and radiotherapy for cancer treatment: (1) the incorporation of PS in form of organic building units allows the generation of singlet oxygen through interaction of the photosensitizer with irradiated light; (2) incorporation of high Z elements, such as Hf, enables the generation of photo electrons through X-ray irradiation. (Center) The idea of a multifunctional NP with high multifunctional efficiency resulting into one simple NP with complete control for the intended purpose.

processes of active agents (e.g., drugs) in the human body to pathogenic areas (e.g., cancer cells), different pH values are especially relevant (e.g., 7.4, blood; 6.2, early endosome in cancer cells; and 5.1, late endosome in cancer cells),37 and therefore, the pH dependence of the release has to be examined. Preiß et al. took a closer look at the loading and release kinetics of fluorescein into/from iron- and chromiumbased MOF NPs over a pH range of 5 to 8.80 A strong dependence of loading/release kinetics on the pH value could be demonstrated, as well as a dependence on the nature of the MOF scaffold itself. The dependence on the MOF’s structure can be explained by the difference in affinity of the guest molecules to different chemical environments in the pores. This understanding can be leveraged by using multivariate MOFs (MTV-MOFs). Multivariate MOFs are constructed by taking the structural backbone of a parent MOF structure, but

incorporating a variety of functionalities to create unique synergistic effects, such as by using OBUs with different functionalities during synthesis.81−84 Dong et al. synthesized different versions of an iron-based MTV-MOF, with three different functionalizations incorporated into the framework with varying ratios.85 Since the strength of host−guest interactions strongly depends on the chemistry within the pores, the ratio of two functional OBUs, one interacting strongly (slow release) and one interacting weakly (fast release) with the guest molecules, enables researchers to vary the release kinetics as desired and make it most beneficial for a particular application (Figure 3d). In this way, pore confinement was possible, and the kinetic release profile of three active agents (DOX, ibuprofen, and rhodamine B) could be tuned. Incorporating the Active Agent into the Organic Building Unit. The adsorption of active agents into the porous F


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based MOF with an azobenzene derivative as the OBU, which is associated with antimicrobial activity, and an active agent in the form of nitric oxide (NO), coordinated to unsaturated metal sites (CUS) within the framework.88 With calcium being the metal cation, this MOF is not only highly biocompatible, it even could provide an important mineral for the body as a side effect of degradation, paired with the antimicrobial OBU. Also, the delivery of NO at the biological level is possible, with NO having wound healing, antithrombotic, and antibiotic activities. Levine et al. based their work on a series of isoreticular frameworks (M-MOF-74) that are ubiquitous in the literature.89−93 Using an OBU with the same coordinating functionality but having the benefit of consisting of an FDAapproved anti-inflammatory compound (oszalazine), a new family of expanded MOF-74 materials could be synthesized. The obtained framework features a high drug loading of 86 wt % and degrades under physiological conditions, releasing oszalazine. Due to its large pores, the MOF could additionally be loaded with the model drug phenethylamine (PEA), enabling the MOF to be used as a platform to deliver multiple therapeutic components (Figure 3e). All these examples are clearly driven by the overall vision of a smart NP delivery system with high functionality. Bio-Metal−Organic Frameworks: Assembly of Biocompatible Building Blocks. For the application of any novel nanomaterial in a medical context, we must ensure that the product is safe for human health.45 Using biocompatible

The outstanding features of metal− organic framework materials are their record-setting high surface areas and chemical modifiability, leading to many different potential applications. framework via host−guest interactions is only one potential method of drug delivery using MOF NPs. A different approach is to incorporate the active component directly into the OBU and, therefore, into the MOF’s scaffold, either during synthesis or by using postsynthetic modification (PSM) strategies.52 Liu et al. followed the approach of integrating different chemotherapeutics into the OBU before MOF formation, which were subsequently incorporated into the scaffold of a Zn-based MOF to create nontoxic, biocompatible MOF-based nanotherapeutics (Figure 3e).86 The MOF degradation inside cancer cells ensures the release of the chemotherapeutics, without the risk of premature leakage. This example of a stimuli-responsive drug delivery system responding to an endogenous stimulus was realized by combining degradability and the ability to functionalize the scaffold of the MOF. Hintz et al. modified an Al-based MOF using PSM with different peptide coupling reagents with subsequent covalent attachment of drugs and biomolecules onto the OBU for possible biomedical applications (Figure 3e).87 Miller et al. reported on a calciumG


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described in the previous paragraphs; however, the size of these agents has been limited by the size of the aperture of the pore. This limitation can be overcome and even used advantageously when following the idea of the ship in the bottle. There are two basic ideas for how to fit a ship that is too big for the bottleneck into the bottle belly: either inserting the individual components and building the ship inside the bottle, or building the bottle around the ship. Both ideas basically work for the encapsulation of active agents, however the synthesis of an agent inside the porous structure is challenging. Applying the ship-in-the-bottle strategy requires the disassembly of the scaffold for releasing the active agents, but it also ensures no premature leakage before the decomposition of material and simplifies the nanocarrier through the absence of any cap systems. Combining this idea with the use of bio-MOFs potentially enables researchers to release drugs in a controlled manner, for example, under acidic conditions in cancer cells. Controlled release of the active agent only in tumor regions and not in the bloodstream minimizes off-target side effects.98 Bearing this criterion in mind, Zhuang et al. encapsulated small molecules into the micropores intrinsic to the framework of the biocompatible Zn-based MOF ZIF-8 in a one-pot synthesis.98 The MOF showed stability under physiological conditions but decomposed in acidic medium (for the MFE, see Box 3). Taking this idea a step further, Zheng et al. used a one-pot process for the encapsulation of larger drug and dye molecules into the same Zn-based MOF.99 The basic principle of synthesis is the following: as a first step, the metal ions and the active organic agents self-assemble into coordination polymers. Subsequently, after addition of the OBU, these coordination polymers are disassembled again, and the MOF is formed around the active agents through the assembly of OBUs and IBUs, resulting in the encapsulation of the target molecule. Unlike the carriers synthesized by Zhuang et al.,98 this strategy leads to MOF NPs with a hierarchical pore structure. In addition to the ordered micropores intrinsic to the MOF scaffold, mesopores containing the target molecule, which are tunable in size through variations in concentration of the target molecule, coexist. After the successful encapsulation of small and large molecules, Liang et al. moved to even bigger molecules in the form of biomacromolecules, such as proteins, DNA, and enzymes (Figure 3g). 100 The principle of encapsulation is similar to the process described above; however, instead of the attraction of metal cation to active agents, the high affinity of biomacromolecules for the OBUs of the MOF induces the MOF formation and thus leads to the encapsulation of the macromolecules by a nanoporous MOF shell. The successful encapsulation could be shown for the same Zn-based MOF as for the smaller molecules, as well as for other types of MOFs based on copper, europium, terbium, and iron, showing the general applicability of this strategy. The soachieved protective MOF coating enables the diffusion of substrate molecules to encapsulated enzymes, showing very high conversion rates, while at the same time withstanding extreme, denaturing conditions like increased temperatures or organic solvents. Alsaiari et al. used the same Zn-based MOF but focused on a genome editing platform to be encapsulated, a combination of a protein and an engineered single guide RNA.101 Due to the large protein size and the highly charged RNA component, delivery of the free macromolecules is highly problematic and, once taken up by the cell, endosomal escape followed by translocation into the nucleus is limited. However, both are of paramount importance for successful genetic

building blocks for NP synthesis increases the chances that the final nanoconstruct will be biocompatible, as well, but does not necessarily guarantee it. Nanoparticle toxicity depends not only on the NP composition but also on its size, shape, surface area, surface charge, and dose, and all these properties are mutually connected.43,44 An et al. worked on the maximization of porosity while using biocompatible OBUs at the same time.94 There are different ways to enhance the porosity in MOFs, including extending the OBUs (which, however, carries the risk of interpenetration), or enlarging the IBUs.94 Following the latter strategy, an exclusively mesoporous bio-MOF with extremely low density (0.302 g cm−3) and a record pore volume (4.3 cm3 g−1) could be obtained. This MOF was constructed from zinc-adeninate vertices as IBUs, which are significantly larger than the basic zinc-carboxylate cluster found in other Zn-based MOFs. To improve biocompatibility of IBUs further, replacing potentially toxic transition metal cations with abundant and inexpensieve biofriendly elements such as calcium or magnesium should be considered. However, according to the hard and soft acids and bases (HSAB) theory, these group II elements are hard acids, and therefore, OBUs with hard basicity are required for coordination. As neutral and charge-polarized OBUs usually do not fall into this category, their use for the creation of MOFs is challenging but, from the perspective of biocompatibility, highly desirable.95 With this idea in mind, Noro et al. introduced a new group of OBUs for the coordination to calcium and magnesium ions, made possible by negatively charge-polarized coordinating groups providing hard basicity in otherwise overall neutral ligands.95 Taking these thoughts a step further, the OBUs could also be replaced by naturally occurring ones. This replacement has been shown to be challenging, however, due to the flexibility of these OBUs paired with the multiplicity of coordination geometries and high coordination number of calcium cations. Yang et al. overcame these challenges and constructed two bioMOFs using calcium as the metal cation and the naturally occurring OBUs lactate and acetate.96 They demonstrated the potential use of one of these MOFs as a carrier for fumigants in agriculture, with the active agents being released as a result of the disassembly of the MOF in aqueous solution. Adsorption of these hazardous liquids enables safer handling and transport as well as reduction of pollution due to the possibility of using lower dosages. All the above-mentioned examples maximize biocompatibility by using biocompatible building blocks for the formation of bio-MOFs. Bailey et al. took this concept more literally by forming MOFs with one of the most important groups of biomolecules serving as IBUs: proteins, here in the form of ferritin molecules (Figure 3f).97 Ferritin possesses octahedral symmetry, and metal coordination sites decorate the outer surface, making its use as an IBU possible, while being inherently functional, catalyzing iron biomineralization. Various metal ions, including zinc, can be bound at the surface-exposed coordination sites with high affinity, enabling further coordination by OBUs and the formation of the protein MOF. Remarkably, despite the extreme size mismatch between OBUs (ca. 9 Å long) and IBUs (120 Å diameter), it was possible to form three-dimensional protein lattices in a selfassembling fashion and uncoordinated ferritin nodes remained capable of iron mineralization even after assembly into the protein MOF. Ship-in-the-Bottle Strategy: Encapsulating Active Agents into the Metal−Organic Framework’s Pores. The idea of loading MOFs with active agents has been H


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CONCLUSIONS AND OUTLOOK Since the emergence of nanotechnology, the synthesis of nanoobjects has dramatically changed the functional possibilities of materials from the nano- to the macroworld. Material scientists have shown that the combination of inorganic and organic chemistries in a single material, “MOFs”, offers structural control at the molecular level, tunable porosity, and chemical functionalizability. These features can be exploited throughout the synthesis of smart MOF NPs with the integration of sophisticated inner and outer surface functionalization. In this Perspective, we discussed novel pathways for the introduction of functionalities into the internal MOF backbone itself, leading to more efficient nanocarriers. Integrating functionality into the MOF backbone increases the functionality ratio of the final nanocarrier system (i.e., the ratio of functional units to total building units), leading to a simpler and, consequently, more applicable product. Nanocarriers have come a long way, from simple systems to multifunctional “smart” entities that are able to respond to various stimuli (sometimes simultaneously) and, by virtue of adding more and more functionality to the same particle, also combine treatment with diagnosis in the field of theranostics. However, it should be pointed out that this is not the end of these endeavors. The real-world application of nanocarriers is a multidisciplinary field that requires collaboration between academia and industry at an international level. After synthesizing a nanocarrier with high efficiency, the transition into the clinic has additional requirements, such as characterization of the nanoconstruct, ensuring controlled and reproducible syntheses in compliance with the good manufacturing practice (GMP) guidelines, evaluation of nanotoxicity and biodistribution, as well as performance analyses of the nanocarrier. Requirements for clinical applications and commercialization such as feasible industrial production, cost-effectiveness, and reproducible quality are in conflict with the design of some highly sophisticated and complex multifunctional nanocarrier systems. Therefore, the parameter of multifunctional efficiency has been introduced to support the design of nanocarriers by considering both the degree of functionality and the complexity of the production process at the same time. In summary, this research area combines advanced porous nanocarrier synthesis with the assembly of molecular functional building blocks into multicomponent nanoconstructs to generate a multifunctional nanosystem. Given the feasibility and potential of this concept, we believe that the definition and application of multifunctional efficiency to nano-objects will guide the synthesis of functional NPs in the future.

transfection. To overcome this problem, the authors encapsulated this complex structure with remarkable loading efficiencies (17%) into the MOF and showed enhanced nucleic delivery. Metal−Organic Framework Nanoparticles for Photodynamic Therapy and Radiotherapy for Cancer Treatment. After discussing the application of MOFs for the delivery of active agents, we conclude with the concept of using MOFs for cancer treatment. Photodynamic therapy (PDT) is a minimally invasive treatment that can be used as an alternative to conventional cancer treatments. The basic idea is the following: a nontoxic photosensitizer (PS) is excited through the interaction with light, transferring its energy to other molecules to generate ROSs, such as singlet oxygen, which induces cellular toxicity (Figure 3h1). Many PS molecules, however, have low selectivity and are hydrophobic, making them prone to aggregation in aqueous solution and, hence, reducing their photodynamic efficacy. These limitations can be overcome by using nanocarriers for selective PS delivery or by incorporating the PS into a MOF scaffold.102 In particular, the incorporation of PSs as OBUs into the MOF scaffold is an interesting approach for an efficient platform for energy transfer, as the highly ordered structure brings the PSs in proximity to each other but without direct contact and hence prevents the formation of aggregates.102 Following this idea, Lu et al. synthesized Hf-based MOF NPs with a porphyrin-derived OBU as a highly effective PS for PDT.103 In vivo experiments showed that the incorporation into the robust and porous MOF scaffold minimized the risk of PS aggregation as well as self-quenching of the excited state and, due to the porosity, enabled facile diffusion of the ROS from the framework into the surrounding environment. Further, intersystem crossing between OBU and IBU was promoted, leading to more than 2-fold increases in efficiency of ROS generation compared to the free PS. All these factors enabled the researchers to observe almost complete or, in some cases, total tumor regression in vivo using the PS-MOF, whereas using the PS molecule alone did not show any therapeutic effects, probably due to fast clearance from the tumor site prior to irradiation. Park et al. developed a pillar-layer-structured Zn-based MOF using a photochromic molecule and a PS as OBUs.104 The photochromic molecule shows reversible transformation between open and closed isomers with distinctive energy levels upon photoirradiation and its incorporation into the scaffold enables control over ROS production. The closed isomer provides an alternative pathway for energy transfer after PS excitation, resulting in quenching of singlet oxygen generation. This control might enable better PDT efficacy. If the oxygen level is depleted, reoxygenation of the damaged cancerous tissue can occur. Containing the same PS as OBU, Liu et al. synthesized Hf-based MOF NPs.105 Unlike the other two examples described in this paragraph, Liu et al. exploited the properties of the IBU for radiotherapy (RT) in addition to the use of the OBUs for PDT, achieving highly functionalized MOF NPs (for the MFE, see Box 3). Hafnium was chosen as a high Z element due to its ability to interact with ionizing radiation (i.e., X-rays) to produce photo/auger electrons (Figure 3h2). These electrons enable the generation of reactive free radicals to destroy cancer cells and, therefore, to enhance RT efficacy. Combined therapy of RT, followed by PDT 8 h later (after oxygen recovery), showed strong inhibition of tumor growth and much better efficacy compared to PDT and RT alone.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Ulrich Lächelt: 0000-0002-4996-7592 Stefan Wuttke: 0000-0002-6344-5782 Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS As nanotechnology is a highly interdisciplinary field, the success of one research group is highly dependent on good collaborations with other groups. Therefore, S.W. would like to thank his primary collaborators for valuable contributions to I


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this research (in alphabetic other): Thomas Bein (University of Munich), Thomas Burg (Max Planck Institute for Biophysical Chemistry), Hanna Engelke (University of Munich), Adelheit Godt (University of Bielefeld), Martin Hossann (Thermosome GmbH), Don Lamb (University of Munich), Marjorie Lismont (University of Liège), Ulrich Lüning (University of Kiel), Dana Medina (University of Munich), Silke Meiners (German Research Center for Environmental Health), Wolfgang Parak (University of Hamburg), Michael Peller (Clinical Center Munich, radiology), Joachim Rädler (University of Munich), Nobert Stock (University of Kiel), Angelika Vollmar (University of Munich), Ernst Wagner (University of Munich), Omar Yaghi (UC Berkeley), and, last but not least, all of the former and current members of the “wuttkegroup for science”. R.F. thanks his wife Luiza and son Milo for their continuous support.

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Multifunctional Efficiency: Extending the Concept of Atom Economy to

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